[Effect of keratoplasty on the quality of life of keratoconus patients]. / Effet de la kératoplastie sur la qualité de vie des patients atteints de kératocône.

Corneal deformations caused by keratoconus produce high levels of optical aberration (OA). Despite appropriate optical correction, these alter the quality of vision and diminish the patient's quality of life, especially since the affected population is predominantly young and of working age. When thinning is too severe or corneal transparency too impaired, a corneal transplant may be considered. In this study, we compare the quality of life of patients with keratoconus in the early (stages 1 and 2) or advanced (stages 3 and 4) stages of the Krumeich classification, as well as patients who have had keratoconus treated by keratoplasty. Quality of life was assessed using the NEI-VFQ 25 questionnaire, the most widely used for keratoconus. An aberrometric examination (OQAS®; HD Analyser, Visiometrics, Terrassa, Spain) was also performed to assess patients' quality of vision. Our results show that keratoplasty provides an improvement in quality of life compared with advanced-stage keratoconus in the areas of distance (p=0.0083) and near vision (p=0.029) activities. This improvement also applies to Best-Corrected Visual Acuity (BCVA) (p=0.032) and transparency (OSI) (p=0.049). Our study shows that keratoplasty improves corneal transparency, and it is interesting to note that it improves patients' quality of life over the long term.

A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer's disease.

Many aging individuals accumulate the pathology of Alzheimer's disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration checkpoint response to early pathological changes that restricts further disease progression and preserves cognitive function. Checkpoint activation is mediated by the REST transcriptional repressor, which is induced in cognitively-intact aging humans and AD mouse models at the onset of amyloid ß-protein (Aß) deposition and tau accumulation. REST induction is mediated by the unfolded protein response together with ß-catenin signaling. A consequence of this response is the targeting of REST to genes involved in key pathogenic pathways, resulting in downregulation of gamma secretase, tau kinases, and pro-apoptotic proteins. Deletion of REST in the 3xTg and J20 AD mouse models accelerates Aß deposition and the accumulation of misfolded and phosphorylated tau, leading to neurodegeneration and cognitive decline. Conversely, viral-mediated overexpression of REST in the hippocampus suppresses Aß and tau pathology. Thus, REST mediates a neurodegeneration checkpoint response with multiple molecular targets that may protect against the onset of AD.

Loss of endosomal exchanger NHE6 leads to pathological changes in tau in human neurons.

Disruption of endolysosomal and autophagy-lysosomal systems is increasingly implicated in neurodegeneration. Sodium-proton exchanger 6 (NHE6) contributes to the maintenance of proper endosomal pH, and loss-of function mutations in the X-linked NHE6 lead to Christianson syndrome (CS) in males. Neurodegenerative features of CS are increasingly recognized, with postmortem and clinical data implicating a role for tau. We generated cortical neurons from NHE6 knockout (KO) and isogenic wild-type control human induced pluripotent stem cells. We report elevated phosphorylated and sarkosyl-insoluble tau in NHE6 KO neurons. We demonstrate that NHE6 KO leads to lysosomal and autophagy dysfunction involving reduced lysosomal number and protease activity, diminished autophagic flux, and p62 accumulation. Finally, we show that treatment with trehalose or rapamycin, two enhancers of autophagy-lysosomal function, each partially rescue this tau phenotype. We provide insight into the neurodegenerative processes underlying NHE6 loss of function and into the broader role of the endosome-lysosome-autophagy network in neurodegeneration.

Early lysosome defects precede neurodegeneration with amyloid-ß and tau aggregation in NHE6-null rat brain.

Loss-of-function mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome in males. Christianson syndrome involves endosome dysfunction leading to early cerebellar degeneration, as well as later-onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in post-mortem studies. In addition, there is reported evidence of modulation of amyloid-ß levels in experimental models wherein NHE6 expression was targeted. We have recently shown that loss of NHE6 causes defects in endosome maturation and trafficking underlying lysosome deficiency in primary mouse neurons in vitro. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously-expressed amyloid-ß and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously-expressed (non-transgenic) tau or amyloid-ß. Therefore, to study neurodegeneration in Christianson syndrome and the possibility of amyloid-ß and tau pathology, we generated an NHE6-null rat model of Christianson syndrome using CRISPR-Cas9 genome-editing. Here, we present the sequence of pathogenic events in neurodegenerating NHE6-null male rat brains across the lifespan. NHE6-null rats demonstrated an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observed biochemical and in situ evidence of both amyloid-ß and tau aggregation in the aged NHE6-null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observed tau deposition in both neurons and glia, as has been reported in Christianson syndrome post-mortem studies previously. In summary, this experimental model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously-expressed amyloid-ß and tau. This NHE6-null rat will serve as a new robust model for Christianson syndrome. Furthermore, these studies provide evidence for linkages between endolysosome dysfunction and neurodegeneration involving protein aggregations, including amyloid-ß and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer's disease and related dementias.

COVID-19 vaccine boosters for young adults: a risk benefit assessment and ethical analysis of mandate policies at universities.

In 2022, students at North American universities with third-dose COVID-19 vaccine mandates risk disenrolment if unvaccinated. To assess the appropriateness of booster mandates in this age group, we combine empirical risk-benefit assessment and ethical analysis. To prevent one COVID-19 hospitalisation over a 6-month period, we estimate that 31 207-42 836 young adults aged 18-29 years must receive a third mRNA vaccine. Booster mandates in young adults are expected to cause a net harm: per COVID-19 hospitalisation prevented, we anticipate at least 18.5 serious adverse events from mRNA vaccines, including 1.5-4.6 booster-associated myopericarditis cases in males (typically requiring hospitalisation). We also anticipate 1430-4626 cases of grade ≥3 reactogenicity interfering with daily activities (although typically not requiring hospitalisation). University booster mandates are unethical because they: (1) are not based on an updated (Omicron era) stratified risk-benefit assessment for this age group; (2) may result in a net harm to healthy young adults; (3) are not proportionate: expected harms are not outweighed by public health benefits given modest and transient effectiveness of vaccines against transmission; (4) violate the reciprocity principle because serious vaccine-related harms are not reliably compensated due to gaps in vaccine injury schemes; and (5) may result in wider social harms. We consider counterarguments including efforts to increase safety on campus but find these are fraught with limitations and little scientific support. Finally, we discuss the policy relevance of our analysis for primary series COVID-19 vaccine mandates.

Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors.

We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology. The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aß and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain. The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD.

Understanding Panic Buying Through an Integrated Psychodynamic Lens.

Previous literature has identified panic buying as often being a response to environmental stressors. In early 2020, we saw an increase in panic buying as a response to a real and/or perceived lack of resources due to COVID-19. Although panic buying has a long history, there is a lack of literature to provide a psychological understanding of the phenomenon. During the early days of COVID-19 clients presented with fear and uncertainty. These negative emotions were, in part, a response to a real shortage of basic supplies. However, the panic response led to behaviors that, for some individuals, resulted in atypical buying patterns. From a therapeutic perspective, one can consider behavioral and psychodynamic explanations and interventions, and how this impacts the associated behaviors. This article will focus on psychodynamic understandings of panic buying as a response to events that result in negative emotions. By providing a psychodynamic understanding of panic buying, authors hope to contribute to the therapy of clients presenting with related behaviors and their associated negative affect.

[Safety and efficiency of epithelium-off accelerated corneal cross-linking for progressive keratoconus in pediatric patients]. / Efficacité et tolérance du cross-linking cornéen épithélium-off accéléré dans le traitement du kératocône évolutif de l'enfant.

In adults, the management of keratoconus has evolved in recent years to achieve a well-codified treatment algorithm. The technique of cross-linking (CXL) has allowed us to stabilize the progression of keratoconus and has been largely developed. It is very effective, with few postoperative complications. Currently, there is no specific keratoconus management protocol for children. As we already know that keratoconus usually evolves more rapidly in children, we might consider whether a stabilizing treatment should be proposed as first-line therapy at the time of diagnosis. We carried out a retrospective study including patients less than 18 years of age with keratoconus who consulted the ophthalmology department at Edouard Herriot hospital in Lyon between 2013 and 2017. The main study parameter was whether or not CXL was performed. The other parameters were gender, age, ethnicity, eye rubbing, presence or absence of atopic disease, maximum keratometry (Kmax), minimal pachymetry, best corrected visual acuity (BCVA) and spherical equivalent. Forty-eight eyes of 34 patients were included. We found that two-thirds of the patients were Caucasian boys. Half of the patients had allergies, and over 60% of patients rubbed their eyes regularly. Only six percent of patients had a family history of keratoconus. The mean age of the patients was 14 (7-18) years at the time of diagnosis. Thirty-four eyes of 22 patients underwent CXL, for a total of 71% of our cohort. No postoperative complications occurred. After CXL, there was no significant difference in minimum pachymetry (455.6±37.25µm vs. 453.45±42.6µm after treatment (P=0.71)) or Kmax (50.23±7.17D vs. 50.99±7.01D after treatment (P=0.058)). There was a significant improvement in BCVA (from 0.30±0.3LogMar to 0.17±0.17LogMar after CXL (P=0.024)) and spherical equivalent (-1.91±2.1D to -2.54±1.89D after treatment (P=0.009)). The mean duration of follow-up was 32.2 months (12-59). CXL shows long-term disease stabilization in children with keratoconus. Nevertheless, this technique is indicated only for progressive keratoconus. Early diagnosis and management are essential in this population where the disease is rapidly changing. Treatment of atopy and performance of corneal topography when a child has irregular astigmatism should become automatic for early detection of this disease.

Pentagalloyl glucose (PGG) partially prevents arterial mechanical changes due to elastin degradation.

BACKGROUND: Elastic fibers are composed primarily of the protein elastin and they provide reversible elasticity to the large arteries. Degradation of elastic fibers is a common histopathology in aortic aneurysms. Pentagalloyl glucose (PGG) has been shown to bind elastin and stabilize elastic fibers in some in vitro studies and in vivo models of abdominal aortic aneurysms, however its effects on native arteries are not well described. OBJECTIVE: Perform detailed studies of the biomechanical effects of PGG on native arteries and the preventative capabilities of PGG for elastin degraded arteries. METHODS: We treated mouse carotid arteries with PGG, elastase (ELA), and PGG+ELA and compared the wall structure, solid mechanics, and fluid transport properties to untreated (UNT) arteries. RESULTS: We found that PGG alone decreased compliance compared to UNT arteries, but did not affect any other structural or biomechanical measures. Mild (30 sec) ELA treatment caused collapse and fragmentation of the elastic lamellae, plastic deformation, decreased compliance, increased modulus, and increased hydraulic conductance of the arterial wall compared to UNT. PGG+ELA treatment partially protected from all of these changes, in particular the plastic deformation. PGG mechanical protection varied considerably across PGG+ELA samples and appeared to correlate with the structural changes. CONCLUSIONS: Our results provide important considerations for the effects of PGG on native arteries and a baseline for further biomechanical studies on preventative elastic fiber stabilization.

A process evaluation of the improving wisely intervention: a peer-to-peer data intervention to reduce overuse in surgery.

BACKGROUND: The Improving Wisely intervention is a peer-to-peer audit and feedback intervention to reduce overuse of Mohs Micrographic Surgery (MMS). The objective of this study was to conduct a process evaluation to evaluate Mohs surgeons' perceptions of the implementation quality and perceived impact of the Improving Wisely intervention. METHODS: Surgeons in the Improving Wisely intervention arm, comprised of members of the American College of Mohs Surgeons (ACMS) who co-led the intervention, were invited to complete surveys and key informant interviews. Participants described perceptions of implementation quality (evaluated via dose, quality of implementation, reach and participant responsiveness), perceived impact of the Improving Wisely intervention (evaluated on a 1-5 Likert and qualitatively), and barriers and facilitators to changing surgeons' clinical practice patterns to reduce Mohs overuse. RESULTS: Seven hundred thirty-seven surgeons participated in the survey. 89% were supportive of the intervention. Participants agreed that the intervention would improve patient care and reduce the annual costs of Mohs surgery. Thirty surgeons participated in key informant interviews. 93% were interested in receiving additional data reports in the future. Participants recommended the reports be disseminated annually, that the reports be expanded to include appropriateness data, and that the intervention be extended to non ACMS members. Six themes identifying factors impacting potential MMS overuse were identified. CONCLUSIONS: Participants were strongly supportive of the intervention. We present the template used to design and implement the Improving Wisely intervention and provide suggestions for specialty societies interested in leading similar quality improvement interventions among their members.

Measurement of the Spin Absorption Anisotropy in Lateral Spin Valves.

The spin absorption process in a ferromagnetic material depends on the spin orientation relative to the magnetization. Using a ferromagnet to absorb the pure spin current created within a lateral spin valve, we evidence and quantify a sizable orientation dependence of the spin absorption in Co, CoFe, and NiFe. These experiments allow us to determine the spin-mixing conductance, an elusive but fundamental parameter of the spin-dependent transport. We show that the obtained values cannot be understood within a model considering only the Larmor, transverse decoherence, and spin diffusion lengths, and rather suggest that the spin-mixing conductance is actually limited by the Sharvin conductance.

Host shifting and host sharing in a genus of specialist flies diversifying alongside their sunflower hosts.

Congeneric parasites are unlikely to specialize on the same tissues of the same host species, likely because of strong multifarious selection against niche overlap. Exceptions where >1 congeneric species use the same tissues reveal important insights into ecological factors underlying the origins and maintenance of diversity. Larvae of sunflower maggot flies in the genus Strauzia feed on plants in the family Asteraceae. Although Strauzia tend to be host specialists, some species specialize on the same hosts. To resolve the origins of host sharing among these specialist flies, we used reduced representation genomic sequencing to infer the first multilocus phylogeny of genus Strauzia. Our results show that Helianthus tuberosus and Helianthus grosseserratus each host three different Strauzia species and that the flies co-occurring on a host are not one another's closest relatives. Though this pattern implies that host sharing is most likely the result of host shifts, these may not all be host shifts in the conventional sense of an insect moving onto an entirely new plant. Many hosts of Strauzia belong to a clade of perennial sunflowers that arose 1-2 MYA and are noted for frequent introgression and hybrid speciation events. Our divergence time estimates for all of the Helianthus-associated Strauzia are within this same time window (<1 MYA), suggesting that rapid and recent adaptive introgression and speciation in Helianthus may have instigated the diversification of Strauzia, with some flies converging upon a single plant host after their respective ancestral host plants hybridized to form a new sunflower species.

An engineered PET depolymerase to break down and recycle plastic bottles.

Present estimates suggest that of the 359 million tons of plastics produced annually worldwide1, 150-200 million tons accumulate in landfill or in the natural environment2. Poly(ethylene terephthalate) (PET) is the most abundant polyester plastic, with almost 70 million tons manufactured annually worldwide for use in textiles and packaging3. The main recycling process for PET, via thermomechanical means, results in a loss of mechanical properties4. Consequently, de novo synthesis is preferred and PET waste continues to accumulate. With a high ratio of aromatic terephthalate units-which reduce chain mobility-PET is a polyester that is extremely difficult to hydrolyse5. Several PET hydrolase enzymes have been reported, but show limited productivity6,7. Here we describe an improved PET hydrolase that ultimately achieves, over 10 hours, a minimum of 90 per cent PET depolymerization into monomers, with a productivity of 16.7 grams of terephthalate per litre per hour (200 grams per kilogram of PET suspension, with an enzyme concentration of 3 milligrams per gram of PET). This highly efficient, optimized enzyme outperforms all PET hydrolases reported so far, including an enzyme8,9 from the bacterium Ideonella sakaiensis strain 201-F6 (even assisted by a secondary enzyme10) and related improved variants11-14 that have attracted recent interest. We also show that biologically recycled PET exhibiting the same properties as petrochemical PET can be produced from enzymatically depolymerized PET waste, before being processed into bottles, thereby contributing towards the concept of a circular PET economy.

Observation of Large Unidirectional Rashba Magnetoresistance in Ge(111).

Relating magnetotransport properties to specific spin textures at surfaces or interfaces is an intense field of research nowadays. Here, we investigate the variation of the electrical resistance of Ge(111) grown epitaxially on semi-insulating Si(111) under the application of an external magnetic field. We find a magnetoresistance term that is linear in current density j and magnetic field B, hence, odd in j and B, corresponding to a unidirectional magnetoresistance. At 15 K, for I=10 µA (or j=0.33 A m^{-1}) and B=1 T, it represents 0.5% of the zero field resistance, a much higher value compared to previous reports on unidirectional magnetoresistance (UMR). We ascribe the origin of this magnetoresistance to the interplay between the externally applied magnetic field and the pseudomagnetic field generated by the current applied in the spin-splitted subsurface states of Ge(111). This unidirectional magnetoresistance is independent of the current direction with respect to the Ge crystal axes. It progressively vanishes, either using a negative gate voltage due to carrier activation into the bulk (without spin-splitted bands), or by increasing the temperature due to the Rashba energy splitting of the subsurface states lower than ∼58k_{B}. We believe that UMR could be used as a powerful probe of the spin-orbit interaction in a wide range of materials.

Gas reactions under intrapore condensation regime within tailored metal-organic framework catalysts.

Production of 1-butene, a major monomer in polymer industry, is dominated by homogeneous protocols via ethylene dimerization. Homogeneous catalysts can achieve high selectivity but require large amounts of activators and solvents, and exhibit poor recyclability; in turn, heterogeneous systems are robust but lack selectivity. Here we show how the precise engineering of metal-organic frameworks (MOFs) holds promise for a sustainable process. The key to the (Ru)HKUST-1 MOF activity is the intrapore reactant condensation that enhances ethylene dimerization with high selectivity (> 99% 1-butene) and high stability (> 120 h) in the absence of activators and solvents. According to spectroscopy, kinetics, and modeling, the engineering of defective nodes via controlled thermal approaches rules the activity, while intrapore ethylene condensation accounts for selectivity and stability. The combination of well-defined actives sites with the concentration effect arising from condensation regimes paves the way toward the development of robust MOF catalysts for diverse gas-phase reactions.

Anatomy of a Neotropical insect radiation.

BACKGROUND: Much evolutionary theory predicts that diversity arises via both adaptive radiation (diversification driven by selection against niche-overlap within communities) and divergence of geographically isolated populations. We focus on tropical fruit flies (Blepharoneura, Tephritidae) that reveal unexpected patterns of niche-overlap within local communities. Throughout the Neotropics, multiple sympatric non-interbreeding populations often share the same highly specialized patterns of host use (e.g., flies are specialists on flowers of a single gender of a single species of host plants). Lineage through time (LTT) plots can help distinguish patterns of diversification consistent with ecologically limited adaptive radiation from those predicted by ecologically neutral theories. Here, we use a time-calibrated phylogeny of Blepharoneura to test the hypothesis that patterns of Blepharoneura diversification are consistent with an "ecologically neutral" model of diversification that predicts that diversification is primarily a function of time and space. RESULTS: The Blepharoneura phylogeny showed more cladogenic divergence associated with geography than with shifts in host-use. Shifts in host-use were associated with ~ 20% of recent splits (< 3 Ma), but > 60% of older splits (> 3 Ma). In the overall tree, gamma statistic and maximum likelihood model fitting showed no evidence of diversification rate changes though there was a weak signature of slowing diversification rate in one of the component clades. CONCLUSIONS: Overall patterns of Blepharoneura diversity are inconsistent with a traditional explanation of adaptive radiation involving decreases in diversification rates associated with niche-overlap. Sister lineages usually use the same host-species and host-parts, and multiple non-interbreeding sympatric populations regularly co-occur on the same hosts. We suggest that most lineage origins (phylogenetic splits) occur in allopatry, usually without shifts in host-use, and that subsequent dispersal results in assembly of communities composed of multiple sympatric non-interbreeding populations of flies that share the same hosts.

[Entrustable professional activities : Promising concept in postgraduate medical education]. / "Entrustable professional activities" : Zukunftsweisendes Konzept für die ärztliche Weiterbildung.

Entrustable professional activities (EPAs) are characterized as self-contained units of work in a given typical clinical context, which may be entrusted to a trainee for independent execution at a certain point of training. An example could be the intraoperative anesthesia management of an ASA 1 patient for an uncomplicated surgical intervention as an EPA in early postgraduate anesthesia training. The EPAs can be described as an evolution of a competency-based medical educational concept, applying the concept of the competencies of a person to specific workplace contexts. In this way the expected level of skills and supervision at a certain stage of training have a more practical meaning and the danger of fragmentation of individual competencies in the competence-based model is avoided. It is a more holistic view of a trainee. Experience with this new concept is so far limited, therefore, further studies are urgently needed to determine whether and how EPAs can contribute to improvements in further training.

Differential time to positivity of central and peripheral blood cultures is inaccurate for the diagnosis of Staphylococcus aureus long-term catheter-related sepsis.

OBJECTIVES: Differential time to positivity of cultures of blood drawn simultaneously from central venous catheter and peripheral sites is widely used to diagnose catheter-related bloodstream infections without removing the catheter. However, the accuracy of this technique for some pathogens, such as Staphylococcus aureus, is debated in routine practice. METHODS: In a 320-bed reference cancer centre, the charts of patients with at least one blood culture positive for S. aureus among paired blood cultures drawn over a six-year period were studied retrospectively. Microbiological data were extracted from the prospectively compiled database of the microbiology unit. Data concerning the 149 patients included were reviewed retrospectively by independent physicians blinded to the absolute and differential times to positivity, in order to establish or refute the diagnosis of catheter-related sepsis. Due to missing data, 48 charts were excluded, so 101 cases were actually analysed. The diagnosis was established in 62 cases, refuted in 15 cases and inconclusive in the remaining 24 cases. RESULTS: For the 64 patients with both central and peripheral positive blood cultures, the differential positivity time was significantly greater for patients with catheter-related bloodstream infections due to S. aureus (P<0.02). However, because of the high number of false-negative cases, the classic cut-off limit of 120 min showed 100% specificity but only 42% sensitivity for the diagnosis of catheter-related bloodstream infection due to S. aureus. CONCLUSIONS: These results strongly suggest that despite its high specificity, the differential time to positivity may not be reliable to rule out catheter-related bloodstream infection due to S. aureus.

Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability.

Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aß, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aß plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable) and caudal fates (relatively spared) in AD. We find that both the generation of Aß and the responsiveness of TAU to Aß are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD.