Martin Gardner's minimum no-3-in-a-line problem

In Martin Gardner's October, 1976 Mathematical Games column in Scientific American, he posed the following problem: "What is the smallest number of [queens] you can put on a board of side n such that no [queen] can be added without creating three in a row, a column, or a diagonal?" We use the Combinatorial Nullstellensatz to prove that this number is at least n, except in the case when n is congruent to 3 modulo 4, in which case one less may suffice. A second, more elementary proof is also offered in the case that n is even.Comment: 11 pages; lower bound in main theorem corrected to n-1 (from n) in the case of n congruent to 3 mod 4, minor edits, added journal referenc

Investigating a Potential Causal Relationship Between Maternal Blood Pressure During Pregnancy and Future Offspring Cardiometabolic Health

Observational epidemiological studies have reported that higher maternal blood pressure (BP) during pregnancy is associated with increased future risk of offspring cardiometabolic disease. However, it is unclear whether this association represents a causal relationship through intrauterine mechanisms. We used a Mendelian randomization (MR) framework to examine the relationship between unweighted maternal genetic scores for systolic BP and diastolic BP and a range of cardiometabolic risk factors in the offspring of up to 29 708 genotyped mother-offspring pairs from the UKB study (UK Biobank) and the HUNT study (Trøndelag Health). We conducted similar analyses in up to 21 423 father-offspring pairs from the same cohorts. We confirmed that the BP-associated genetic variants from the general population sample also had similar effects on maternal BP during pregnancy in independent cohorts. We did not detect any association between maternal (or paternal) unweighted genetic scores and cardiometabolic offspring outcomes in the meta-analysis of UKB and HUNT after adjusting for offspring genotypes at the same loci. We find little evidence to support the notion that maternal BP is a major causal risk factor for adverse offspring cardiometabolic outcomes in later life

Assessing hippocampal functional reserve in temporal lobe epilepsy:A multi-voxel pattern analysis of fMRI data

Assessing the functional reserve of key memory structures in the medial temporal lobes (MTL) of pre-surgical patients with intractable temporal lobe epilepsy (TLE) remains a challenge. Conventional functional MRI (fMRI) memory paradigms have yet to fully convince of their ability to confidently assess the risk of a post-surgical amnesia. An alternative fMRI analysis method, multi-voxel pattern analysis (MVPA), focuses on the patterns of activity across voxels in specific brain regions that are associated with individual memory traces. This method makes it possible to investigate whether the hippocampus and related structures contralateral to any proposed surgery are capable of laying down and representing specific memories. Here we used MVPA-fMRI to assess the functional integrity of the hippocampi and MTL in patients with long-standing medically refractory TLE associated with unilateral hippocampal sclerosis (HS). Patients were exposed to movie clips of everyday events prior to scanning, which they subsequently recalled during high-resolution fMRI. MTL structures were delineated and pattern classifiers were trained to learn the patterns of brain activity across voxels associated with each memory. Predictable patterns of activity across voxels associated with specific memories could be detected in MTL structures, including the hippocampus, on the side contralateral to the HS, indicating their functional viability. By contrast, no discernible memory representations were apparent in the sclerotic hippocampus, but adjacent MTL regions contained detectable information about the memories. These findings suggest that MVPA in fMRI memory studies of TLE can indicate hippocampal functional reserve and may be useful to predict the effects of hippocampal resection in individual patients

Antigen glycosylation regulates efficacy of CAR T cells targeting CD19

While chimeric antigen receptor (CAR) T cells targeting CD19 can cure a subset of patients with B cell malignancies, most patients treated will not achieve durable remission. Identification of the mechanisms leading to failure is essential to broadening the efficacy of this promising platform. Several studies have demonstrated that disruption of CD19 genes and transcripts can lead to disease relapse after initial response; however, few other tumor-intrinsic drivers of CAR T cell failure have been reported. Here we identify expression of the Golgi-resident intramembrane protease Signal peptide peptidase-like 3 (SPPL3) in malignant B cells as a potent regulator of resistance to CAR therapy. Loss of SPPL3 results in hyperglycosylation of CD19, an alteration that directly inhibits CAR T cell effector function and suppresses anti-tumor cytotoxicity. Alternatively, over-expression of SPPL3 drives loss of CD19 protein, also enabling resistance. In this pre-clinical model these findings identify post-translational modification of CD19 as a mechanism of antigen escape from CAR T cell therapy

Kinetic changes during a six-week minimal footwear and gait-retraining intervention in runners.

An evaluation of a six-week Combined minimal footwear transition and gait-retraining combination vs. gait retraining only on impact characteristics and leg stiffness. Twenty-four trained male runners were randomly assigned to either (1) Minimalist footwear transition Combined with gait-retraining over a six-week period ("Combined" group; n = 12) examined in both footwear, or (2) a gait-retraining group only with no minimalist footwear exposure ("Control"; n = 12). Participants were assessed for loading rate, impact peak, vertical, knee and ankle stiffness, and foot-strike using 3D and kinetic analysis. Loading rate was significantly higher in the Combined group in minimal shoes in pre-tests compared to a Control (P ≤ 0.001), reduced significantly in the Combined group over time (P ≤ 0.001), and was not different to the Control group in post-tests (P = 0.16). The impact peak (P = 0.056) and ankle stiffness reduced in both groups (P = 0.006). Loading rate and vertical stiffness was higher in minimalist footwear than conventional running shoes both pre (P ≤ 0.001) and post (P = 0.046) the intervention. There has a higher tendency to non-rearfoot strike in both interventions, but more acute changes in the minimalist footwear. A Combined intervention can potentially reduce impact variables. However, higher loading rate initially in minimalist footwear may increase the risk of injury in this condition

Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration

Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors

The effects of extensive grazing on the vegetation of a landscape-scale restoration site

The Wicken Fen Vision (Cambridgeshire, UK) is a landscape-scale habitat restoration project that uses process-driven, open-ended approaches to develop habitats on highly degraded and drained peat soils of former intensive arable land. The project land is extensively grazed with herds of free-roaming, minimally managed herds of Highland cattle and Konik horses. In one 119 ha area, seven 25m x 25 m grazing exclosures were erected and vascular plant species were recorded from 2007 to 2017. Plant species data were analysed to (1) compare changes in plant species composition and diversity in grazed and ungrazed areas; (2) use plant species traits and plant-environment associations to explore the nature of changes in plant composition; (3) use remote sensing to explore changes in vegetation structure; (4) examine the influence of land use histories on grazing outcomes in different parts of the site. There was a clear divergence through time between grazed and ungrazed areas, attributed to significantly greater canopy height, Ellenberg L (Light) and Ellenberg N (fertility) values within the exclosures. Species richness was significantly higher in grazed compared with ungrazed areas and species assemblages separated through the study period. After ten years, extensive free-roaming grazing has had significant impacts on vegetation structure and species richness but effects varied across the study site because of differing historical land use

Head injury from falls in children younger than 6 years of age

The risk of serious head injury (HI) from a fall in a young child is ill defined. The relationship between the object fallen from and prevalence of intracranial injury (ICI) or skull fracture is described. Method Cross-sectional study of HIs from falls in children (<6 years) admitted to UK hospitals, analysed according to the object fallen from and associated Glasgow Coma Score (GCS) or alert, voice, pain, unresponsive (AVPU) and CT scan results. Results Of 1775 cases ascertained (median age 18 months, 54.7% boys), 87% (1552) had a GCS=15/AVPU=alert. 19.3% (342) had a CT scan: 32% (110/342) were abnormal; equivalent to 5.9% of the overall population, 16.9% (58) had isolated skull fractures and 13.7% (47) had ICI (49% (23/47) had an associated skull fracture). The prevalence of ICI increased with neurological compromise; however, 12% of children with a GCS=15/AVPU=alert had ICI. When compared to falls from standing, falls from a person's arms (233 children (mean age 1 year)) had a significant relative OR for a skull fracture/ICI of 6.94 (95% CI 3.54 to 13.6), falls from a building (eg, window or attic) (mean age 3 years) OR 6.84 (95% CI 2.65 to 17.6) and from an infant or child product (mean age 21 months) OR 2.75 (95% CI 1.36 to 5.65). Conclusions Most HIs from a fall in these children admitted to hospital were minor. Infants, dropped from a carer's arms, those who fell from infant products, a window, wall or from an attic had the greatest chance of ICI or skull fracture. These data inform prevention and the assessment of the likelihood of serious injury when the object fallen from is known

The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants

Background: It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C>T (rs1130864) and CHD risk in the largest study to date of this association.Methods and Results: We estimated the association of CRP genetic variant +1444C>T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N= 18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95% CI: 1.06, 1.21), and after further adjustment for confounding factors it was 1.07 (95% CI: 1.02, 1.13). Genotype (rs1130864) was associated with circulating CRP; the pooled ratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95% CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95% CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I-2 = 0%, p>0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95% CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95% CI: 0.90, 1.03) per additional T allele (I-2<7.5%, p. 0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95% CI: 0.61, 1.80).Conclusions: We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out

BAAV Transcytosis Requires an Interaction with β-1-4 Linked- Glucosamine and gp96

Cell surface carbohydrates play an important role in virus entry and intracellular trafficking. Bovine Adeno-Associated Virus (BAAV) uses plasma membrane gangliosides for transduction and infection. In addition, independent of the infectious pathway, BAAV also has the ability to pass through barrier epithelia and endothelia using a transcytosis pathway dependent upon the presence of cell surface carbohydrates. Thus, in order to better define the carbohydrate interactions that are necessary for BAAV infection or transcytosis, a glycan microarray composed of both natural and synthetic carbohydrates was probed with HA-tagged BAAV particles. This identified chitotriose, a trimer of β-1-4-linked N-acetyl glucosamine, as having an interaction with BAAV. Competition experiments showed that the BAAV interaction with this carbohydrate is not necessary for infection but is instead important in the transcytosis pathway. The β-1-4-linked N-acetyl glucosamine modification has been reported on gp96, a glycoprotein involved in the transcytosis of bacteria and toxins. Significantly, immunoprecipitation and competition experiments with an anti-gp96 antibody and a soluble form of gp96, respectively, showed this glycoprotein can also interact with BAAV to serve as a receptor for its transcytosis