Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors.

Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry in vivo , or for optimally informative disease modeling and/or therapeutic screening in vitro , it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing inappropriate proneural Neurog2 expression by progenitors. We FACS-purify these genetically accessible progenitors from postnatal mouse cortex and establish a pure culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2 , while antagonizing Olig2 with VP16:Olig2 ). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors, and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo . They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2 -driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from genetically accessible cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.

Large Exchange Coupling Between Localized Spins and Topological Bands in MnBi2 Te4.

Magnetism in topological materials creates phases exhibiting quantized transport phenomena with potential technological applications. The emergence of such phases relies on strong interaction between localized spins and the topological bands, and the consequent formation of an exchange gap. However, this remains experimentally unquantified in intrinsic magnetic topological materials. Here, this interaction is quantified in MnBi2 Te4 , a topological insulator with intrinsic antiferromagnetism. This is achieved by optically exciting Bi-Te p states comprising the bulk topological bands and interrogating the consequent Mn 3d spin dynamics, using a multimodal ultrafast approach. Ultrafast electron scattering and magneto-optic measurements show that the p states demagnetize via electron-phonon scattering at picosecond timescales. Despite being energetically decoupled from the optical excitation, the Mn 3d spins, probed by resonant X-ray scattering, are observed to disorder concurrently with the p spins. Together with atomistic simulations, this reveals that the exchange coupling between localized spins and the topological bands is at least 100 times larger than the superexchange interaction, implying an optimal exchange gap of at least 25 meV in the surface states. By quantifying this exchange coupling, this study validates the materials-by-design strategy of utilizing localized magnetic order to manipulate topological phases, spanning static to ultrafast timescales.

Interlayer magnetophononic coupling in MnBi2Te4.

The emergence of magnetism in quantum materials creates a platform to realize spin-based applications in spintronics, magnetic memory, and quantum information science. A key to unlocking new functionalities in these materials is the discovery of tunable coupling between spins and other microscopic degrees of freedom. We present evidence for interlayer magnetophononic coupling in the layered magnetic topological insulator MnBi2Te4. Employing magneto-Raman spectroscopy, we observe anomalies in phonon scattering intensities across magnetic field-driven phase transitions, despite the absence of discernible static structural changes. This behavior is a consequence of a magnetophononic wave-mixing process that allows for the excitation of zone-boundary phonons that are otherwise 'forbidden' by momentum conservation. Our microscopic model based on density functional theory calculations reveals that this phenomenon can be attributed to phonons modulating the interlayer exchange coupling. Moreover, signatures of magnetophononic coupling are also observed in the time domain through the ultrafast excitation and detection of coherent phonons across magnetic transitions. In light of the intimate connection between magnetism and topology in MnBi2Te4, the magnetophononic coupling represents an important step towards coherent on-demand manipulation of magnetic topological phases.

Extreme Ultraviolet Second Harmonic Generation Spectroscopy in a Polar Metal.

The coexistence of ferroelectricity and metallicity seems paradoxical, since the itinerant electrons in metals should screen the long-range dipole interactions necessary for dipole ordering. The recent discovery of the polar metal LiOsO3 was therefore surprising [as discussed earlier in Y. Shi et al., Nat. Mater. 2013, 12, 1024]. It is thought that the coordination preferences of the Li play a key role in stabilizing the LiOsO3 polar metal phase, but an investigation from the combined viewpoints of core-state specificity and symmetry has yet to be done. Here, we apply the novel technique of extreme ultraviolet second harmonic generation (XUV-SHG) and find a sensitivity to the broken inversion symmetry in the polar metal phase of LiOsO3 with an enhanced feature above the Li K-edge that reflects the degree of Li atom displacement as corroborated by density functional theory calculations. These results pave the way for time-resolved probing of symmetry-breaking structural phase transitions on femtosecond time scales with element specificity.

An evolutionarily conserved Lhx2-Ldb1 interaction regulates the acquisition of hippocampal cell fate and regional identity.

The protein co-factor Ldb1 regulates cell fate specification by interacting with LIM-homeodomain (LIM-HD) proteins in a tetrameric complex consisting of an LDB:LDB dimer that bridges two LIM-HD molecules, a mechanism first demonstrated in the Drosophila wing disc. Here, we demonstrate conservation of this interaction in the regulation of mammalian hippocampal development, which is profoundly defective upon loss of either Lhx2 or Ldb1 Electroporation of a chimeric construct that encodes the Lhx2-HD and Ldb1-DD (dimerization domain) in a single transcript cell-autonomously rescues a comprehensive range of hippocampal deficits in the mouse Ldb1 mutant, including the acquisition of field-specific molecular identity and the regulation of the neuron-glia cell fate switch. This demonstrates that the LHX:LDB complex is an evolutionarily conserved molecular regulatory device that controls complex aspects of regional cell identity in the developing brain.

Preoperative Anemia and Outcomes in Cardiovascular Surgery: Systematic Review and Meta-Analysis.

BACKGROUND: Preoperative anemia is common in patients scheduled for cardiac surgery. However, its effect on postoperative outcomes remains controversial. This meta-analysis aimed to clarify the impact of anemia on outcomes after cardiac surgery. METHODS: A literature search was conducted on MEDLINE, Embase, Cochrane, and Web of Science databases. The primary outcome was 30-day postoperative or in-hospital mortality. Secondary outcomes included acute kidney injury, stroke, blood transfusion, and infection. A meta-analytic model was used to determine the differences in the above postoperative outcomes between anemic and nonanemic patients. RESULTS: Of 1103 studies screened, 22 met the inclusion criteria. Of 114,277 patients, 23,624 (20.6%) were anemic. Anemia was associated with increased mortality (odds ratio [OR], 2.74; 95% confidence interval [CI], 2.32-3.24; I2 = 69.6%; P < .001), acute kidney injury (OR, 3.13; 95% CI, 2.37-4.12; I2 = 71.1%; P < .001), stroke (OR, 1.46; 95% CI, 1.24-1.72; I2 = 21.6%; P < .001), and infection (OR, 2.65; 95% CI, 1.98-3.55; I2 = 46.7%; P < .001). More anemic patients were transfused than nonanemic patients (33.3% vs 11.9%, respectively). No statistically significant association was found between mortality and blood transfusion (OR, 1.35; 95% CI, 0.92-1.98; I2 = 83.7%; P = .12), but we were not able to compare mortality with or without transfusion in those who were or were not anemic. CONCLUSIONS: Preoperative anemia is associated with adverse outcomes after cardiac surgery. These findings support the addition of preoperative anemia to future risk prediction models and as a target for risk modification.

Association Between Anemia and Blood Transfusion With Long-term Mortality After Cardiac Surgery.

BACKGROUND: Preoperative anemia and red blood cell (RBC) transfusion are both associated with in-hospital mortality after cardiac surgery. The aim of this study was to investigate the interactions between preoperative anemia and RBC transfusion and their effect on the long-term survival of patients undergoing cardiac surgery. METHODS: Between 2005 and 2012, 1170 patients with anemia who underwent elective or urgent cardiac surgery were included. A matched group of 1170 nonanemic patients was used as a control group. A binary logistic regression model was used. RESULTS: The median follow-up period was 64 months (range, 0-127). Anemic patients had higher mortality (45%, n = 526) than nonanemic patients (32%, n = 374; P < .001). Preoperative anemia was independently associated with long-term mortality (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.46-2.1; P < .001), with both moderate (OR, 2.27; 95% CI, 1.72-2.99; P < .001) and mild anemia (OR, 1.39; 95% CI, 1.13-1.71; P = .002) contributing significantly. RBC transfusion was not associated with long-term mortality (OR, 1.07; 95% CI, 0.88-1.31; P = .49). There was no interaction between preoperative anemia and RBC transfusion (P = .947). CONCLUSIONS: Long-term mortality is significantly high in patients who are anemic, regardless of their transfusion status. Preoperative anemia is a strong, independent predictor of mortality and therefore should be managed before cardiac surgery.

Intravenous iron does not effectively correct preoperative anaemia in cardiac surgery: a pilot randomized controlled trial.

OBJECTIVES: Preoperative anaemia is a strong predictor of blood transfusion requirements and must be assessed for appropriate optimization before elective surgery. Iron therapy is a transfusion-sparing approach effective for increasing haemoglobin concentrations. However, its role in elective cardiac surgery and the optimal route of administration remain unknown. This single-centre, non-blinded, randomized, controlled trial compared the effectiveness of intravenous ferric carboxymaltose therapy with oral iron for anaemic patients undergoing elective cardiac surgery. METHODS: Fifty anaemic patients scheduled for elective cardiac surgery were randomized to receive either oral or intravenous iron therapy 3-8 weeks preoperatively. Changes in haemoglobin concentration were measured. Blood transfusion and postoperative outcome data were collected. RESULTS: Preoperative median increases in haemoglobin were 1.0 g/l (interquartile range -3.25 to 7.25 g/l) and 3.0 g/l (interquartile range -1.25 to 6.25 g/l) for patients receiving intravenous and oral iron, respectively (P = 0.42). The median first 12-h blood loss was significantly higher in the intravenous group (655 ml; interquartile range 162-1540 ml) compared to the oral group (313 ml; interquartile range 150-1750 ml; P < 0.007). Median increments in serum ferritin were superior for the intravenous group (median difference 313 µg/l; interquartile range 228-496) compared to the oral group (median difference 5.5 µg/l; interquartile range -1.4 to 19.4; P < 0.001). CONCLUSIONS: Increases in ferritin after intravenous iron administration were significantly greater than those after oral iron administration. There was no significant difference in haemoglobin increments between groups. Despite significantly higher intraoperative blood loss in the group receiving intravenous iron, blood transfusion requirements for both groups were not statistically different. CLINICAL TRIAL REGISTRATION: ISRCTN22158788.

Developmentally primed cortical neurons maintain fidelity of differentiation and establish appropriate functional connectivity after transplantation.

Repair of complex CNS circuitry requires newly incorporated neurons to become appropriately, functionally integrated. One approach is to direct differentiation of endogenous progenitors in situ, or ex vivo followed by transplantation. Prior studies find that newly incorporated neurons can establish long-distance axon projections, form synapses and functionally integrate in evolutionarily old hypothalamic energy-balance circuitry. We now demonstrate that postnatal neocortical connectivity can be reconstituted with point-to-point precision, including cellular integration of specific, molecularly identified projection neuron subtypes into correct positions, combined with development of appropriate long-distance projections and synapses. Using optogenetics-based electrophysiology, experiments demonstrate functional afferent and efferent integration of transplanted neurons into transcallosal projection neuron circuitry. Results further indicate that 'primed' early postmitotic neurons, including already fate-restricted deep-layer projection neurons and/or plastic postmitotic neuroblasts with partially fate-restricted potential, account for the predominant population of neurons capable of achieving this optimal level of integration.

LHX2 Interacts with the NuRD Complex and Regulates Cortical Neuron Subtype Determinants Fezf2 and Sox11.

In the developing cerebral cortex, sequential transcriptional programs take neuroepithelial cells from proliferating progenitors to differentiated neurons with unique molecular identities. The regulatory changes that occur in the chromatin of the progenitors are not well understood. During deep layer neurogenesis, we show that transcription factor LHX2 binds to distal regulatory elements of Fezf2 and Sox11, critical determinants of neuron subtype identity in the mouse neocortex. We demonstrate that LHX2 binds to the nucleosome remodeling and histone deacetylase histone remodeling complex subunits LSD1, HDAC2, and RBBP4, which are proximal regulators of the epigenetic state of chromatin. When LHX2 is absent, active histone marks at the Fezf2 and Sox11 loci are increased. Loss of LHX2 produces an increase, and overexpression of LHX2 causes a decrease, in layer 5 Fezf2 and CTIP2-expressing neurons. Our results provide mechanistic insight into how LHX2 acts as a necessary and sufficient regulator of genes that control cortical neuronal subtype identity. SIGNIFICANCE STATEMENT: The functional complexity of the cerebral cortex arises from an array of distinct neuronal subtypes with unique connectivity patterns that are produced from common progenitors. This study reveals that transcription factor LHX2 regulates the numbers of specific cortical output neuron subtypes by controlling the genes that are required to produce them. Loss or increase in LHX2 during neurogenesis is sufficient to increase or decrease, respectively, a particular subcerebrally projecting population. Mechanistically, LHX2 interacts with chromatin modifying protein complexes to edit the chromatin landscape of its targets Fezf2 and Sox11, which regulates their expression and consequently the identities of the neurons produced. Thus, LHX2 is a key component of the control network for producing neurons that will participate in cortical circuitry.

Preassessment Interview Improves the Efficacy and Safety of Bowel Preparation for Colonoscopy.

Aim. To determine whether preassessment improves bowel preparation quality and prevents renal deterioration for chronic kidney disease (CKD) patients. Methods. Data was collected prospectively starting in January 2011 for 12 months. Patients were divided according to the presence or absence of preassessment and stratified to one of three risk groups based on patient's comorbidities and identified risk factors for poor bowel preparation; group 1 had no risk factors, group 2 had 1 risk factor, and group 3 patients had 2 or more risk factors. The association between preassessment and bowel preparation quality was analyzed using binary logistic regression. Results. 1840 colonoscopies were carried out during the period. Total number analyzed was 1704. 404 patients were preassessed. Preassessment patients had significantly better bowel preparation across all groups (OR 1.605; p = 0.002). Group 3 patients were 52% more likely to have good bowel preparation (p = 0.04) if they had been preassessed. Eighty-eight patients were identified with an eGFR < 60 mL/min. There was a significant difference in the eGFR percentage change between patients with preassessment and those without (p = 0.006). Conclusions. Face-to-face preassessment appears to improve the quality of bowel preparation and aids in minimizing the risk of renal injury in patients with CKD.

Anemia in cardiac surgery: next target for mortality and morbidity improvement?

OBJECTIVE: To assess the effects of preoperative anemia on outcomes of cardiac surgery and to explore the trend in mortality over an 8-year period. METHODS: During the study period (2005-2012), all 1170 patients undergoing elective or urgent cardiac surgery and classed as anemic were included. A matched group of non-anemic 1170 patients was used as a control group. Postoperative outcomes were compared between the 2 groups. The association between preoperative anemia and postoperative outcomes was analyzed using a logistic regression model. RESULTS: Compared with patients without anemia, the need for airway support (15% vs. 12%, p = 0.05), renal replacement therapy (13% vs. 8%, p < 0.01) and the rate of in-hospital surgical site infection (9% vs. 7%, p = 0.05) were higher in the anemic group. Anemia was associated with greater need for renal replacement therapy (odds ratio = 1.76, confidence interval: 1.21-2.37, p = 0.002) and prolonged (> 7 days) hospital stay (odds ratio = 1.21, confidence interval: 0.97-1.51, p = 0.08). The blood transfusion rate (54% vs. 33%, p < 0.01) and hospital mortality (5.6% vs. 3.5%, p = 0.02) were higher in the anemic group. Over the 8-year period, there was a significant improvement in mortality in the non-anemic group (from 6.5% to 1.6%) but less so in the anemic group (from 6.7% to 4.7%). CONCLUSION: Anemia impacts significantly on morbidity and mortality after cardiac surgery, with less improvement over time compared to patients without anemia. Preoperative correction of anemia, when feasible, could potentially help to improve cardiac surgery outcomes.

Ethnic variation in colorectal cancer risk following a positive faecal occult blood test in an English bowel cancer screening programme centre.

BACKGROUND AND AIMS: The literature on colorectal cancer (CRC) screening and ethnic diversity is dominated by studies from the USA. There are no such published data from the UK bowel cancer screening programme (BCSP) population. The Wolverhampton Bowel Cancer Screening Centre serves a population of 900,000 in the Black Country and South Staffordshire. South Asians (SA) comprise 9% of the population. We aimed to determine the effects of ethnicity and sex on the risk for cancer or adenoma detected by colonoscopy following a positive faecal occult blood test over a 5-year period (2007-2011). METHODS: Data were collected from the prospectively maintained BCSP cohort. South Asian patients were identified and compared with those of non-South Asian ethnicity, and colonoscopy outcomes were determined. RESULTS: A total of 3552 participants underwent BCSP colonoscopy (non-South Asian=3363; SA=189). There were 271 cancers (7.6%) detected within the non-South Asian group and seven cancers (0.2%) in the South Asian population (P<0.05). The probability of colon cancer is higher [odds ratio (OR)=3.84, P<0.05] in non-South Asians compared with South Asians. Patients in the 65-70-year age group have the highest risk (OR=1.60; P<0.05) for CRC. During the study 1313 adenomas were detected. A total of 771 high-risk and intermediate-risk adenomas were detected in the non-South Asian group, and 14 were detected in the South Asian group. The risk of adenoma in non-South Asians is six times higher than in South Asians (OR=5.99, P<0.001) following positive faecal occult blood testing. CONCLUSION: There are fewer colorectal cancers in South Asians compared with the non-South Asian population in this regional study. This is the first such study in the BCSP population.

Iron and colorectal cancer: evidence from in vitro and animal studies.

Iron is a vital trace element essential for mammalian life. It is involved in numerous biological and cellular processes such as oxygen transport, oxidative phosphorylation, and DNA synthesis, as well as cell cycle progression and growth. Normal and neoplastic cells have similar qualitative requirements for iron. In addition, research shows that iron promotes cancer cell growth. An adequate balance of iron is, therefore, critical for health. In states of iron deficiency, anemia can develop, whereas iron excess increases oxidative stress in body tissues, leading to lipid, protein, and DNA damage via the Fenton reaction, which results in the synthesis of hydroxyl radicals and other oxidants. It is thought that some of these processes are implicated in the pathogenesis of colorectal cancer. This review provides the clinician with an up-to-date summary of the recent advances in this field using established in vitro and animal models.

Anatomic and molecular development of corticostriatal projection neurons in mice.

Corticostriatal projection neurons (CStrPN) project from the neocortex to ipsilateral and contralateral striata to control and coordinate motor programs and movement. They are clinically important as the predominant cortical population that degenerates in Huntington's disease and corticobasal ganglionic degeneration, and their injury contributes to multiple forms of cerebral palsy. Together with their well-studied functions in motor control, these clinical connections make them a functionally, behaviorally, and clinically important population of neocortical neurons. Little is known about their development. "Intratelencephalic" CStrPN (CStrPNi), projecting to the contralateral striatum, with their axons fully within the telencephalon (intratelencephalic), are a major population of CStrPN. CStrPNi are of particular interest developmentally because they share hodological and axon guidance characteristics of both callosal projection neurons (CPN) and corticofugal projection neurons (CFuPN); CStrPNi send axons contralaterally before descending into the contralateral striatum. The relationship of CStrPNi development to that of broader CPN and CFuPN populations remains unclear; evidence suggests that CStrPNi might be evolutionary "hybrids" between CFuPN and deep layer CPN-in a sense "chimeric" with both callosal and corticofugal features. Here, we investigated the development of CStrPNi in mice-their birth, maturation, projections, and expression of molecular developmental controls over projection neuron subtype identity.

Lhx2 regulates a cortex-specific mechanism for barrel formation.

LIM homeodomain transcription factors are critical regulators of early development in multiple systems but have yet to be examined for a role in circuit formation. The LIM homeobox gene Lhx2 is expressed in cortical progenitors during development and also in the superficial layers of the neocortex in maturity. However, analysis of Lhx2 function at later stages of cortical development has been hampered by severe phenotypes associated with early loss of function. We identified a particular Cre-recombinase line that acts in the cortical primordium after its specification is complete, permitting an analysis of Lhx2 function in neocortical lamination, regionalization, and circuit formation by selective elimination of Lhx2 in the dorsal telencephalon. We report a profound disruption of cortical neuroanatomical and molecular features upon loss of Lhx2 in the cortex from embryonic day 11.5. A unique feature of cortical circuitry, the somatosensory barrels, is undetectable, and molecular patterning of cortical regions appears disrupted. Surprisingly, thalamocortical afferents innervate the mutant cortex with apparently normal regional specificity. Electrophysiological recordings reveal a loss of responses evoked by stimulation of individual whiskers, but responses to simultaneous stimulation of multiple whiskers were present, suggesting that thalamic afferents are unable to organize the neurocircuitry for barrel formation because of a cortex-specific requirement of Lhx2. We report that Lhx2 is required for the expression of transcription factor paired box gene 6, axon guidance molecule Ephrin A5, and the receptor NMDA receptor 1. These genes may mediate Lhx2 function in the formation of specialized neurocircuitry necessary for neocortical function.

An unusual case of gastric outlet obstruction caused by tuberculosis: challenges in diagnosis and treatment.

Gastroduodenal tuberculosis (GDTB) is rare in the West. Its presentation can be non-specific and often mimics other more common conditions such as peptic ulcer disease, malignancy and Crohn's disease. Our case describes a 33-year-old Indian immigrant who presented with a 3-year history of dyspepsia and underwent balloon dilation for gastric outlet obstruction (GOO). While biopsies from the duodenum revealed only non-caseating granuloma, a high index of suspicion was maintained and colonoscopy, performed despite the absence of lower gastrointestinal symptoms, revealed a single discrete nodular and ulcerated area in the proximal transverse colon; this eventually grew Mycobacterium tuberculosis. Our patient avoided undergoing major surgery and was successfully treated with balloon dilation and antitubercular medication. We highlight the importance of having a concerted, proactive approach to diagnosis. We discuss the therapeutic challenges involving this rare condition and explain the rationale for high-dose antisecretory therapy.

Lmo4 establishes rostral motor cortex projection neuron subtype diversity.

The mammalian neocortex is parcellated into anatomically and functionally distinct areas. The establishment of area-specific neuronal diversity and circuit connectivity enables distinct neocortical regions to control diverse and specialized functional outputs, yet underlying molecular controls remain largely unknown. Here, we identify a central role for the transcriptional regulator Lim-only 4 (Lmo4) in establishing the diversity of neuronal subtypes within rostral mouse motor cortex, where projection neurons have particularly diverse and multi-projection connectivity compared with caudal motor cortex. In rostral motor cortex, we report that both subcerebral projection neurons (SCPN), which send projections away from the cerebrum, and callosal projection neurons (CPN), which send projections to contralateral cortex, express Lmo4, whereas more caudal SCPN and CPN do not. Lmo4-expressing SCPN and CPN populations are comprised of multiple hodologically distinct subtypes. SCPN in rostral layer Va project largely to brainstem, whereas SCPN in layer Vb project largely to spinal cord, and a subset of both rostral SCPN and CPN sends second ipsilateral caudal (backward) projections in addition to primary projections. Without Lmo4 function, the molecular identity of neurons in rostral motor cortex is disrupted and more homogenous, rostral layer Va SCPN aberrantly project to the spinal cord, and many dual-projection SCPN and CPN fail to send a second backward projection. These molecular and hodological disruptions result in greater overall homogeneity of motor cortex output. Together, these results identify Lmo4 as a central developmental control over the diversity of motor cortex projection neuron subpopulations, establishing their area-specific identity and specialized connectivity.