Outcomes Following Total Hip Arthroplasty in Patients Who Have Von Willebrand Disease Depend on Postoperative Anticoagulation.

BACKGROUND: Von Willebrand disease (VWD) is the most common congenital bleeding disorder. This autosomal dominant condition arises from quantitative or qualitative defects of Von Willebrand factor. To our knowledge, this study leveraged a national database to characterize the largest VWD cohort of total hip arthroplasty (THA) patients to date, assessing 90-day postoperative adverse events and 5-year revision-free survival. METHODS: Adult patients who underwent primary THA for osteoarthritis were identified from January 2010 to October 2021 in a nationwide database. Patients who had and did not have VWD were matched (4:1) on age, sex, and Elixhauser Comorbidity Index and compared with multivariable logistic regression. Patients were then categorized based upon venous thromboembolism (VTE) chemoprophylaxis prescription patterns to compare bleeding and thrombotic adverse events. RESULTS: Of 544,851 THA patients, VWD was identified in 309 patients (0.06%). The matched cohorts contained 1,221 patients who did not have VWD and 306 patients who have VWD. On multivariable analysis, VWD patients had increased odds of 90-day VTE (odds ratio [OR] = 1.86) and hematoma (OR = 3.40) (P < .05 for all). No difference in 5-year revision-free survival was found. The VWD patients receiving aspirin or no prescriptions had greater odds of VTE (OR = 2.39, P = .048). Those on other chemoprophylaxis agents had greater odds of hematoma (OR = 4.84, P = .006). CONCLUSIONS: Patients with VWD undergoing THA had increased odds of 90-day VTE if using aspirin or no prescriptions, or hematoma if using other chemoprophylaxis. There is a delicate balancing act of clotting versus bleeding that must be considered in managing such patients, but it was reassuring that no difference in overall 5-year revision-free survival was found.

Total shoulder arthroplasty in patients with Factor V Leiden.

BACKGROUND: Anatomic and reverse total shoulder arthroplasty (TSA) are effective treatment options for end-stage glenohumeral osteoarthritis. However, consideration for pre-existing conditions must be taken into account. Factor V Leiden (FVL), the most common inherited thrombophilia, is one such condition that predisposes to a prothrombotic state and may affect perioperative and longer-term outcomes following TSA. METHODS: Adult patients undergoing primary TSA for osteoarthritis indication were identified in the 2010 through October 2021 PearlDiver M157 database. Patients with or without FVL were matched at a 1:4 ratio based on age, sex, and Elixhauser Comorbidity Index. Ninety-day adverse events and five-year revision rates were assessed and compared with multivariable logistic regression and rank-log tests, respectively. Finally, the relative use and bleeding/clotting outcomes were assessed based on venous thromboembolic (VTE) prophylactic agents utilized, with categories defined as (1) warfarin, heparin, or direct oral anticoagulant (DOAC) or (2) aspirin/no prescriptions found. RESULTS: Of 104,258 TSA patients, FVL was identified for 283 (0.27%). Based on matching, 1,081 patients without FVL and 272 patients with FVL were selected. Multivariable analyses demonstrated that those with FVL displayed independently greater odds ratios (ORs) of deep vein thrombosis (DVT, OR=9.50, p<0.0001), pulmonary embolism (PE, OR = 10.10, p<0.0001), and pneumonia (OR=2.43, p=0.0019). Further, these events contributed to the increased odds of aggregated minor (OR = 1.95, p=0.0001), serious (OR=6.38, p<0.0001), and all (OR=3.51, p<0.0001) adverse events. All other individual 90-day adverse events, as well as 5-year revision rates, were not different between the study groups. When compared to matched patients without FVL on the same anticoagulant agents, FVL patients on warfarin/heparin/DOAC agents demonstrated lesser odds of 90-day DVT and PE (OR=4.25, p<0.0001 and OR=2.54, p=0.0065) than those on aspirin/no prescriptions found (OR=7.64 and OR=21.95, p<0.0001 for both). Interestingly, those on VTE prophylactic agents were not at greater odds of bleeding complications (hematoma or transfusion). DISCUSSION AND CONCLUSIONS: TSA patients with FVL present a difficult challenge to shoulder reconstruction surgeons. The current study highlights the strong risk of VTE that was reduced but still significantly elevated for those with stronger classes of VTE chemoprophylaxis. Acknowledging this risk is important for surgical planning and patient counseling, but also noted was the reassurance of similar 5-year revision rates for those with versus without FVL.

Femoral Head Core Decompressions: Characterization of Subsequent Conversion to Total Hip Arthroplasty and Related Complications.

BACKGROUND: Core decompression is a minimally invasive joint-preserving approach for early-stage osteonecrosis. The rate at which core decompression patients require total hip arthroplasty (THA) and rates of perioperative adverse outcomes have not been well-characterized. METHODS: Adult patients undergoing core decompression and/or THA with osteonecrosis of the femoral head were identified from the 2015 to 2021 Q3 PearlDiver M157 database. Those undergoing THA without or with antecedent core decompression were identified and matched 4:1 on age, sex, and Elixhauser Comorbidity Index. Postoperative 90-day adverse events were compared with multivariable analysis. Five-year rates of revision, dislocation, and periprosthetic fracture were compared by the Kaplan-Meier curve and log-rank tests. RESULTS: Core decompressions were identified for 3,025 patients of whom 387 (12.8%) went on to THA within 5 years (64% within the first year). The median time from initial core decompression to THA was 252 days. For THA, 26,209 adults were identified and 387 had prior core decompression. After matching, there were 1,320 without core decompression and 339 with core decompression. No statistically significant differences were observed in 90-day postoperative adverse events or 5-year rates of revision, dislocation, or periprosthetic fracture. CONCLUSION: Core decompression may be an option for patients with osteonecrosis and does not seem to affect THA outcomes if required later.

Strain-switchable field-induced superconductivity.

Field-induced superconductivity is a rare phenomenon where an applied magnetic field enhances or induces superconductivity. Here, we use applied stress as a control switch between a field-tunable superconducting state and a robust non-field-tunable state. This marks the first demonstration of a strain-tunable superconducting spin valve with infinite magnetoresistance. We combine tunable uniaxial stress and applied magnetic field on the ferromagnetic superconductor Eu(Fe0.88Co0.12)2As2 to shift the field-induced zero-resistance temperature between 4 K and a record-high value of 10 K. We use x-ray diffraction and spectroscopy measurements under stress and field to reveal that strain tuning of the nematic order and field tuning of the ferromagnetism act as independent control parameters of the superconductivity. Combining comprehensive measurements with DFT calculations, we propose that field-induced superconductivity arises from a novel mechanism, namely, the uniquely dominant effect of the Eu dipolar field when the exchange field splitting is nearly zero.

Deep scRNA sequencing reveals a broadly applicable Regeneration Classifier and implicates antioxidant response in corticospinal axon regeneration.

Despite substantial progress in understanding the biology of axon regeneration in the CNS, our ability to promote regeneration of the clinically important corticospinal tract (CST) after spinal cord injury remains limited. To understand regenerative heterogeneity, we conducted patch-based single-cell RNA sequencing on rare regenerating CST neurons at high depth following PTEN and SOCS3 deletion. Supervised classification with Garnett gave rise to a Regeneration Classifier, which can be broadly applied to predict the regenerative potential of diverse neuronal types across developmental stages or after injury. Network analyses highlighted the importance of antioxidant response and mitochondrial biogenesis. Conditional gene deletion validated a role for NFE2L2 (or NRF2), a master regulator of antioxidant response, in CST regeneration. Our data demonstrate a universal transcriptomic signature underlying the regenerative potential of vastly different neuronal populations and illustrate that deep sequencing of only hundreds of phenotypically identified neurons has the power to advance regenerative biology.

Prenatal alcohol exposure dysregulates spinal and circulating immune cell circular RNA expression in adult female rats with chronic sciatic neuropathy.

Alcohol consumption during pregnancy is associated with Fetal Alcohol Spectrum Disorders (FASD) that results in a continuum of central nervous system (CNS) deficits. Emerging evidence from both preclinical and clinical studies indicate that the biological vulnerability to chronic CNS disease in FASD populations is driven by aberrant neuroimmune actions. Our prior studies suggest that, following minor nerve injury, prenatal alcohol exposure (PAE) is a risk factor for developing adult-onset chronic pathological touch sensitivity or allodynia. Allodynia in PAE rats occurs concurrently with heightened proinflammatory peripheral and spinal glial-immune activation. However, minor nerve-injured control rats remain non-allodynic, and corresponding proinflammatory factors are unaltered. A comprehensive molecular understanding of the mechanism(s) that underlie PAE-induced proinflammatory bias during adulthood remains elusive. Non-coding circular RNAs (circRNAs) are emerging as novel modulators of gene expression. Here, we hypothesized that PAE induces dysregulation of circRNAs that are linked to immune function under basal and nerve-injured conditions during adulthood. Utilizing a microarray platform, we carried out the first systematic profiling of circRNAs in adult PAE rats, prior to and after minor nerve injury. The results demonstrate a unique circRNA profile in adult PAE rats without injury; 18 circRNAs in blood and 32 spinal circRNAs were differentially regulated. Following minor nerve injury, more than 100 differentially regulated spinal circRNAs were observed in allodynic PAE rats. Bioinformatic analysis identified that the parental genes of these circRNAs are linked to the NF-κB complex, a central transcription factor for pain-relevant proinflammatory cytokines. Quantitative real-time PCR was employed to measure levels of selected circRNAs and linear mRNA isoforms. We have validated that circVopp1 was significantly downregulated in blood leukocytes in PAE rats, concurrent with downregulation of Vopp1 mRNA levels. Spinal circVopp1 levels were upregulated in PAE rats, regardless of nerve injury. Additionally, PAE downregulated levels of circItch and circRps6ka3, which are linked to immune regulation. These results demonstrate that PAE exerts long-lasting dysregulation of circRNA expression in blood leukocytes and the spinal cord. Moreover, the spinal circRNA expression profile following peripheral nerve injury is differentially modulated by PAE, potentially contributing to PAE-induced neuroimmune dysregulation.

Spontaneous orbital polarization in the nematic phase of FeSe.

The origin of nematicity in FeSe remains a critical outstanding question towards understanding unconventional superconductivity in proximity to nematic order. To understand what drives the nematicity, it is essential to determine which electronic degree of freedom admits a spontaneous order parameter independent from the structural distortion. Here we use X-ray linear dichroism at the Fe K pre-edge to measure the anisotropy of the 3d orbital occupation as a function of in situ applied stress and temperature across the nematic transition. Along with using X-ray diffraction to precisely quantify the strain state, we reveal a lattice-independent, spontaneously ordered orbital polarization within the nematic phase, as well as an orbital polarizability that diverges as the transition is approached from above. These results provide strong evidence that spontaneous orbital polarization serves as the primary order parameter of the nematic phase.

The Correlation Between Pelvic Motion and Lumbar Motion in Patients Presenting With a Lumbar Spinal Pathology: Implications for Assessing Dislocation Risk in Total Hip Arthroplasty.

Background: Arthroplasty surgeons use the change in sacral slope (ΔSS) from sitting to standing as a measure of spinal motion. The relationship between ΔSS and the change in lumbar lordosis (ΔLL), an established spinal motion measure, has not been well studied. This study aims to determine the correlation between ΔSS and ΔLL. Methods: Consecutive patients presenting to a spine clinic from 2020 to 2021 at a single institution were retrospectively studied. Standing and sitting lateral radiographs were measured for SS and LL. Patients were divided using ΔSS and ΔLL into stiff (0°-9°), normal (10°-30°), or hypermobile (>30°) category. Patients with a ΔSS-determined normal or hypermobile spine but a ΔLL-determined stiff spine were compared to the rest of the cohort. Results: Overall, 100 patients were included. Of these patients, 47% had the same classification when looking at ΔSS and ΔLL, whereas 53% had conflicting classifications. Twenty percent of patients had a ΔSS-determined normal or hypermobile spine but ΔLL-determined stiff spine. The correlation between ΔSS and ΔLL was 0.510 (P < .001). When isolating patients who underwent lumbar fusion, the correlation between ΔSS and ΔLL was 0.345 (P < .001). Conclusions: ΔSS has a moderate correlation with ΔLL in patients presenting for evaluation of their lumbar spine but low correlation in patients with lumbar fusion. In our cohort, 20% of patients had a ΔSS-determined normal or hypermobile spine but a ΔLL-determined stiff spine, representing a potential high-risk dislocation cohort not captured by ΔSS alone. Arthroplasty surgeons should revisit classifying spinal motion based solely on ΔSS.

Probing regenerative heterogeneity of corticospinal neurons with scRNA-Seq.

The corticospinal tract (CST) is clinically important for the recovery of motor functions after spinal cord injury. Despite substantial progress in understanding the biology of axon regeneration in the central nervous system (CNS), our ability to promote CST regeneration remains limited. Even with molecular interventions, only a small proportion of CST axons regenerate1. Here we investigate this heterogeneity in the regenerative ability of corticospinal neurons following PTEN and SOCS3 deletion with patch-based single cell RNA sequencing (scRNA-Seq)2,3, which enables deep sequencing of rare regenerating neurons. Bioinformatic analyses highlighted the importance of antioxidant response and mitochondrial biogenesis along with protein translation. Conditional gene deletion validated a role for NFE2L2 (or NRF2), a master regulator of antioxidant response, in CST regeneration. Applying Garnett4, a supervised classification method, to our dataset gave rise to a Regenerating Classifier (RC), which, when applied to published scRNA-Seq data, generates cell type- and developmental stage-appropriate classifications. While embryonic brain, adult dorsal root ganglion and serotonergic neurons are classified as Regenerators, most neurons from adult brain and spinal cord are classified as Non-regenerators. Adult CNS neurons partially revert to a regenerative state soon after injury, which is accelerated by molecular interventions. Our data indicate the existence of universal transcriptomic signatures underlying the regenerative abilities of vastly different neuronal populations, and further illustrate that deep sequencing of only hundreds of phenotypically identified CST neurons has the power to reveal new insights into their regenerative biology.

Targeting PTEN but not SOCS3 resists an age-dependent decline in promoting axon sprouting.

Axonal repair is critical for functional recovery after injury of the CNS. We previously reported that neuronal PTEN deletion exhibits an age-dependent decline in promoting axon regeneration from the corticospinal tract (CST). How sprouting of uninjured axons, a naturally occurring form of axonal repair, is impacted by age is unknown. We assessed CST sprouting after unilateral pyramidotomy in PTEN and/or SOCS3-deleted mice at different ages. While PTEN deletion enhances sprouting independently of age, SOCS3 deletion loses its sprouting-promoting effect with age. The synergistic effect of PTEN/SOCS3 co-deletion on CST sprouting is rapidly lost with increased age. Overall, promoting sprouting appears more robust across age than regeneration, yet distinct molecular pathways are differentially impacted by age. Importantly, six-week delayed PTEN deletion promotes CST sprouting across age groups, supporting a clinically relevant time frame for this neural repair strategy independently of age.

Controllable Emergent Spatial Spin Modulation in Sr_{2}IrO_{4} by In Situ Shear Strain.

Symmetric anisotropic interaction can be ferromagnetic and antiferromagnetic at the same time but for different crystallographic axes. We show that the competition of anisotropic interactions of orthogonal irreducible representations can be a general route to obtain new exotic magnetic states. We demonstrate it here by observing the emergence of a continuously tunable 12-layer spatial spin modulation when distorting the square-lattice planes in the quasi-two-dimensional antiferromagnetic Sr_{2}IrO_{4} under in situ shear strain. This translation-symmetry-breaking phase is a result of an unusual strain-activated anisotropic interaction which is at the fourth order and competing with the inherent quadratic anisotropic interaction. Such a mechanism of competing anisotropy is distinct from that among the ferromagnetic, antiferromagnetic, and/or the Dzyaloshinskii-Moriya interactions, and it could be widely applicable and highly controllable in low-dimensional magnets.

The transport-structural correspondence across the nematic phase transition probed by elasto X-ray diffraction.

Electronic nematicity in iron pnictide materials is coupled to both the lattice and the conducting electrons, which allows both structural and transport observables to probe nematic fluctuations and the order parameter. Here we combine simultaneous transport and X-ray diffraction measurements with in-situ tunable strain (elasto X-ray diffraction) to measure the temperature dependence of the shear modulus and elastoresistivity above the nematic transition and the spontaneous orthorhombicity and resistivity anisotropy below the nematic transition, all within a single sample of Ba(Fe0.96Co0.04)2As2. The ratio of transport to structural quantities is nearly temperature independent over a 74 K range and agrees between the ordered and disordered phases. These results show that elasto X-ray diffraction is a powerful technique to probe the nemato-elastic and nemato-transport couplings, which have important implications to the nearby superconductivity. It also enables the measurement in the large strain limit, where the breakdown of the mean-field description reveals the intertwined nature of nematicity.

Conditional inactivation of Foxc1 and Foxc2 in neural crest cells leads to cardiac abnormalities.

Cardiac neural crest cells (cNCCs) are required for normal heart development. cNCCs are a multipotent and migratory cell lineage that differentiates into multiple cell types. cNCCs migrate into the developing heart to contribute to the septation of the cardiac outflow tract (OFT). Foxc1 and Foxc2 are closely related members of the FOX (Forkhead box) transcription factor family and are expressed in cNCC during heart development. However, the precise role of Foxc1 and Foxc2 in cNCCs has yet to be fully described. We found that compound NCC-specific Foxc1;Foxc2 mutant embryos exhibited persistent truncus arteriosus (PTA), ventricular septal defects (VSDs), and thinning of the ventricular myocardium. Loss of Foxc1/c2 expression in cNCCs resulted in abnormal patterns of cNCC migration into the OFT without the formation of the aorticopulmonary septum. Further, loss of Foxc1 expression in cNCCs resulted in normal OFT development but abnormal ventricular septal formation. In contrast, loss of Foxc2 expression in NCCs led to no obvious cardiac abnormalities. Together, we provide evidence that Foxc1 and Foxc2 in cNCCs are cooperatively required for proper cNCC migration, the formation of the OFT septation, and the development of the ventricles. Our data also suggests that Foxc1 expression may play a larger role in ventricular development compared to Foxc2.

The LFA-1 antagonist BIRT377 reverses neuropathic pain in prenatal alcohol-exposed female rats via actions on peripheral and central neuroimmune function in discrete pain-relevant tissue regions.

Previous reports show that moderate prenatal alcohol exposure (PAE) poses a risk factor for developing neuropathic pain following adult-onset peripheral nerve injury in male rats. Recently, evidence suggests that immune-related mechanisms underlying neuropathic pain in females are different compared to males despite the fact that both sexes develop neuropathy of similar magnitude and duration following chronic constriction injury (CCI) of the sciatic nerve. Data suggest that the actions of peripheral T cells play a greater role in mediating neuropathy in females. The goal of the current study is to identify specificity of immune cell and cytokine changes between PAE and non-PAE neuropathic females by utilizing a well-characterized rodent model of sciatic nerve damage, in an effort to unmask unique signatures of immune-related factors underlying the risk of neuropathy from PAE. Cytokines typically associated with myeloid cell actions such as interleukin (IL)-1ß, tumor necrosis factor (TNF), IL-6, IL-4 and IL-10 as well as the neutrophil chemoattractant CXCL1, are examined. In addition, transcription factors and cytokines associated with various differentiated T cell subtypes are examined (anti-inflammatory FOXP3, proinflammatory IL-17A, IL-21, ROR-γt, interferon (IFN)-γ and T-bet). Lymphocyte function associated antigen 1 (LFA-1) is an adhesion molecule expressed on peripheral immune cells including T cells, and regulates T cell activation and extravasation into inflamed tissue regions. A potential therapeutic approach was explored with the goal of controlling proinflammatory responses in neuroanatomical regions critical for CCI-induced allodynia by blocking LFA-1 actions using BIRT377. The data show profound development of hindpaw allodynia in adult non-PAE control females following standard CCI, but not following minor CCI, while minor CCI generated allodynia in PAE females. The data also show substantial increases in T cell-associated proinflammatory cytokine mRNA and proteins, along with evidence of augmented myeloid/glial activation (mRNA) and induction of myeloid/glial-related proinflammatory cytokines, CCL2, IL-1ß and TNF in discrete regions along the pain pathway (damaged sciatic nerve, dorsal root ganglia; DRG, and spinal cord). Interestingly, the characteristic anti-inflammatory IL-10 protein response to nerve damage is blunted in neuropathic PAE females. Moreover, T cell profiles are predominantly proinflammatory in neuropathic Sac and PAE females, augmented levels of Th17-specific proinflammatory cytokines IL-17A and IL-21, as well as the Th1-specific factor, T-bet, are observed. Similarly, the expression of RORγt, a critical transcription factor for Th17 cells, is detected in the spinal cord of neuropathic females. Blocking peripheral LFA-1 actions with intravenous (i.v.) BIRT377 reverses allodynia in Sac and PAE rats, dampens myeloid (IL-1ß, TNF, CXCL1)- and T cell-associated proinflammatory factors (IL-17A and RORγt) and spinal glial activation. Moreover, i.v. BIRT377 treatment reverses the blunted IL-10 response to CCI observed only in neuropathic PAE rats and elevates FOXP3 in pain-reversed Sac rats. Unexpectedly, intrathecal BIRT377 treatment is unable to alter allodynia in either Sac or PAE neuropathic females. Together, these data provide evidence that: 1) fully differentiated proinflammatory Th17 cells recruited at the sciatic nerve, DRGs and lumbar spinal cord may interact with the local environment to shape the immune responses underlying neuropathy in female rats, and, 2) PAE primes peripheral and spinal immune responses in adult females. PAE is a risk factor in females for developing peripheral neuropathy after minor nerve injury.

Anomalous magnetoresistance due to longitudinal spin fluctuations in a Jeff = 1/2 Mott semiconductor.

As a hallmark of electronic correlation, spin-charge interplay underlies many emergent phenomena in doped Mott insulators, such as high-temperature superconductivity, whereas the half-filled parent state is usually electronically frozen with an antiferromagnetic order that resists external control. We report on the observation of a positive magnetoresistance that probes the staggered susceptibility of a pseudospin-half square-lattice Mott insulator built as an artificial SrIrO3/SrTiO3 superlattice. Its size is particularly large in the high-temperature insulating paramagnetic phase near the Néel transition. This magnetoresistance originates from a collective charge response to the large longitudinal spin fluctuations under a linear coupling between the external magnetic field and the staggered magnetization enabled by strong spin-orbit interaction. Our results demonstrate a magnetic control of the binding energy of the fluctuating particle-hole pairs in the Slater-Mott crossover regime analogous to the Bardeen-Cooper-Schrieffer-to-Bose-Einstein condensation crossover of ultracold-superfluids.

Targeting the ß2-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure.

Recently, moderate prenatal alcohol exposure (PAE) was shown to be a risk factor for peripheral neuropathy following minor nerve injury. This effect coincides with elevated spinal cord astrocyte activation and ex vivo immune cell reactivity assessed by proinflammatory cytokine interleukin (IL) -1ß protein expression. Additionally, the ß2-integrin adhesion molecule, lymphocyte function-associated antigen-1 (LFA-1), a factor that influences the expression of the proinflammatory/anti-inflammatory cytokine network is upregulated. Here, we examine whether PAE increases the proinflammatory immune environment at specific anatomical sites critical in the pain pathway of chronic sciatic neuropathy; the damaged sciatic nerve (SCN), the dorsal root ganglia (DRG), and the spinal cord. Additionally, we examine whether inhibiting LFA-1 or IL-1ß actions in the spinal cord (intrathecal; i.t., route) could alleviate chronic neuropathic pain and reduce spinal and DRG glial activation markers, proinflammatory cytokines, and elevate anti-inflammatory cytokines. Results show that blocking the actions of spinal LFA-1 using BIRT-377 abolishes allodynia in PAE rats with sciatic neuropathy (CCI) of a 10 or 28-day duration. This effect is observed (utilizing immunohistochemistry; IHC, with microscopy analysis and protein quantification) in parallel with reduced spinal glial activation, IL-1ß and TNFα expression. DRG from PAE rats with neuropathy reveal significant increases in satellite glial activation and IL-1ß, while IL-10 immunoreactivity is reduced by half in PAE rats under basal and neuropathic conditions. Further, blocking spinal IL-1ß with i.t. IL-1RA transiently abolishes allodynia in PAE rats, suggesting that IL-1ß is in part, necessary for the susceptibility of adult-onset peripheral neuropathy caused by PAE. Chemokine mRNA analyses from SCN, DRG and spinal cord reveal that increased CCL2 occurs following CCI injury regardless of PAE and BIRT-377 treatment. These data demonstrate that PAE creates dysregulated proinflammatory IL-1ß and TNFα /IL-10 responses to minor injury in the sciatic-DRG-spinal pain pathway. PAE creates a risk for developing peripheral neuropathies, and LFA-1 may be a novel therapeutic target for controlling dysregulated neuroimmune actions as a consequence of PAE.

Two-dimensional itinerant ferromagnetism in atomically thin Fe3GeTe2.

Discoveries of intrinsic two-dimensional (2D) ferromagnetism in van der Waals (vdW) crystals provide an interesting arena for studying fundamental 2D magnetism and devices that employ localized spins1-4. However, an exfoliable vdW material that exhibits intrinsic 2D itinerant magnetism remains elusive. Here we demonstrate that Fe3GeTe2 (FGT), an exfoliable vdW magnet, exhibits robust 2D ferromagnetism with strong perpendicular anisotropy when thinned down to a monolayer. Layer-number-dependent studies reveal a crossover from 3D to 2D Ising ferromagnetism for thicknesses less than 4 nm (five layers), accompanied by a fast drop of the Curie temperature (TC) from 207 K to 130 K in the monolayer. For FGT flakes thicker than ~15 nm, a distinct magnetic behaviour emerges in an intermediate temperature range, which we show is due to the formation of labyrinthine domain patterns. Our work introduces an atomically thin ferromagnetic metal that could be useful for the study of controllable 2D itinerant ferromagnetism and for engineering spintronic vdW heterostructures5.

Prenatal alcohol exposure is a risk factor for adult neuropathic pain via aberrant neuroimmune function.

BACKGROUND: Clinical studies show that prenatal alcohol exposure (PAE) results in effects that persist into adulthood. Experimental animal models of moderate PAE demonstrate that young adults with PAE display potentiated sensitivity to light touch, clinically termed allodynia, following sciatic nerve chronic constriction injury (CCI) that coincides with heightened spinal glial, spinal macrophage, and peripheral immune responses. However, basal touch sensitivity and corresponding glial and leukocyte activation are unaltered. Therefore, the current study explored whether the enduring pathological consequences of moderate PAE on sensory processing are unmasked only following secondary neural insult. METHODS: In middle-aged (1 year) Long Evans rats that underwent either prenatal saccharin exposure (control) or moderate PAE, we modified the well-characterized model of sciatic neuropathy, CCI, to study the effects of PAE on neuro-immune responses in adult offspring. Standard CCI manipulation required 4 chromic gut sutures, while a mild version applied a single suture loosely ligated around one sciatic nerve. Spinal glial immunoreactivity was examined using immunohistochemistry. The characterization and functional responses of leukocyte populations were studied using flow cytometry and cell stimulation assays followed by quantification of the proinflammatory cytokines interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α). Data were statistically analyzed by ANOVA and unpaired t tests. RESULTS: The current report demonstrates that mild CCI generates robust allodynia only in PAE rats, while the pathological effects of PAE following the application of a standard CCI are revealed by enhanced allodynia and elevated spinal glial activation. Additionally, mild CCI increases spinal astrocyte activation but not microglia, suggesting astrocytes play a larger role in PAE-induced susceptibility to aberrant sensory processing. Leukocyte populations from PAE are altered under basal conditions (i.e., prior to secondary insult), as the distribution of leukocyte populations in lymphoid organs and other regions are different from those of controls. Lastly, following in vitro leukocyte stimulation, only PAE augments the immune response to antigen stimulation as assessed by heightened production of TNF-α and IL-1ß. CONCLUSIONS: These studies demonstrate PAE may prime spinal astrocytes and peripheral leukocytes that contribute to enduring susceptibility to adult-onset neuropathic pain that is not apparent until a secondary insult later in life.

Sea Level Rise Induced Arsenic Release from Historically Contaminated Coastal Soils.

Climate change-induced perturbations in the hydrologic regime are expected to impact biogeochemical processes, including contaminant mobility and cycling. Elevated levels of geogenic and anthropogenic arsenic are found along many coasts around the world, most notably in south and southeast Asia but also in the United States, particularly along the Mid-Atlantic coast. The mechanism by and the extent to which arsenic may be released in contaminated coastal soils due to sea level rise are unknown. Here we show a series of data from a coastal arsenic-contaminated soil exposed to sea and river waters in biogeochemical microcosm reactors across field-validated redox conditions. We find that reducing conditions lead to arsenic release from historically contaminated coastal soils through reductive dissolution of arsenic-bearing mineral oxides in both sea and river water inundations, with less arsenic release from seawater scenarios than river water due to inhibition of oxide dissolution. For the first time, we systematically display gradation of solid phase soil-arsenic speciation across defined redox windows from reducing to oxidizing conditions in natural waters by combining biogeochemical microcosm experiments and X-ray absorption spectroscopy. Our results demonstrate the threat of sea level rise stands to impact arsenic release from contaminated coastal soils by changing redox conditions.

Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels.

A growing body of evidence indicates that prenatal alcohol exposure (PAE) may predispose individuals to secondary medical disabilities later in life. Animal models of PAE reveal neuroimmune sequelae such as elevated brain astrocyte and microglial activation with corresponding region-specific changes in immune signaling molecules such as cytokines and chemokines. The aim of this study was to evaluate the effects of moderate PAE on the development and maintenance of allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in adult male rat offspring. Because CCI allodynia requires the actions of glial cytokines, we analyzed lumbar spinal cord glial and immune cell surface markers indicative of their activation levels, as well as sciatic nerve and dorsal root ganglia (DRG) cytokines in PAE offspring in adulthood. While PAE did not alter basal sensory thresholds before or after sham manipulations, PAE significantly potentiated adult onset and maintenance of allodynia. Microscopic analysis revealed exaggerated astrocyte and microglial activation, while flow cytometry data demonstrated increased proportions of immune cells with cell surface major histocompatibility complex II (MHCII) and ß-integrin adhesion molecules, which are indicative of PAE-induced immune cell activation. Sciatic nerves from CCI rats revealed that PAE potentiated the proinflammatory cytokines interleukin (IL)-1ß, IL-6 and tumor necrosis factor-alpha (TNFα) protein levels with a simultaneous robust suppression of the anti-inflammatory cytokine, IL-10. A profound reduction in IL-10 expression in the DRG of PAE neuropathic rats was also observed. Taken together, our results provide novel insights into the vulnerability that PAE produces for adult-onset central nervous system (CNS) pathological conditions from peripheral nerve injury.