Chronosequence of invasion reveals minimal losses of population genomic diversity, niche expansion, and trait divergence in the polyploid, leafy spurge.

Rapid evolution may play an important role in the range expansion of invasive species and modify forecasts of invasion, which are the backbone of land management strategies. However, losses of genetic variation associated with colonization bottlenecks may constrain trait and niche divergence at leading range edges, thereby impacting management decisions that anticipate future range expansion. The spatial and temporal scales over which adaptation contributes to invasion dynamics remain unresolved. We leveraged detailed records of the ~130-year invasion history of the invasive polyploid plant, leafy spurge (Euphorbia virgata), across ~500 km in Minnesota, U.S.A. We examined the consequences of range expansion for population genomic diversity, niche breadth, and the evolution of germination behavior. Using genotyping-by-sequencing, we found some population structure in the range core, where introduction occurred, but panmixia among all other populations. Range expansion was accompanied by only modest losses in sequence diversity, with small, isolated populations at the leading edge harboring similar levels of diversity to those in the range core. The climatic niche expanded during most of the range expansion, and the niche of the range core was largely non-overlapping with the invasion front. Ecological niche models indicated that mean temperature of the warmest quarter was the strongest determinant of habitat suitability and that populations at the leading edge had the lowest habitat suitability. Guided by these findings, we tested for rapid evolution in germination behavior over the time course of range expansion using a common garden experiment and temperature manipulations. Germination behavior diverged from the early to late phases of the invasion, with populations from later phases having higher dormancy at lower temperatures. Our results suggest that trait evolution may have contributed to niche expansion during invasion and that distribution models, which inform future management planning, may underestimate invasion potential without accounting for evolution.

A Unique Case of Exploratory Laparotomy in the Setting of Large Bowel Obstruction Led to the Detection of Pancreatic Carcinoma.

Pancreatic adenocarcinoma is the second most common gastrointestinal cancer after colon cancer. There is a delay in the detection of pancreatic adenocarcinoma as it remains asymptomatic in many individuals until it has metastasized to different parts of the body. We present a case of pancreatic cancer causing a large bowel obstruction in a 78-year-old female, detected during an exploratory laparotomy. Despite the increased incidence of pancreatic cancer, there are no screening guidelines that have been enacted for early detection and cure. Practicing clinicians should keep pancreatic cancer in the differential in high-risk individuals.

A Unique Interaction of Methotrexate and Nitrofurantoin Resulting in Irreversible Pulmonary Fibrosis.

Pulmonary toxicity is the most well-known severe complication related to both methotrexate and nitrofurantoin, which can present as acute, subacute, and chronic. Rheumatoid arthritis is also known to cause pulmonary disease if left untreated. In this report, we present a unique case of a 94-year-old female being treated with methotrexate for several years and then treated with nitrofurantoin in the setting of rheumatoid arthritis and chronic urinary tract infections, resulting in irreversible pulmonary fibrosis, which can further cause more susceptibility to infections and pneumonia. Drug-drug interactions are common in polypharmacy and a patient's history should be analyzed thoroughly before prescribing any new medication that can cause more harm to the patient than good.

The Unifying Hypothesis of Alzheimer's Disease: Heparan Sulfate Proteoglycans/Glycosaminoglycans Are Key as First Hypothesized Over 30 Years Ago.

The updated "Unifying Hypothesis of Alzheimer's disease" (AD) is described that links all the observed neuropathology in AD brain (i.e., plaques, tangles, and cerebrovascular amyloid deposits), as well as inflammation, genetic factors (involving ApoE), "AD-in-a-Dish" studies, beta-amyloid protein (Aß) as a microbial peptide; and theories that bacteria, gut microflora, gingivitis and viruses all play a role in the cause of AD. The common link is the early accumulation of heparan sulfate proteoglycans (HSPGs) and heparan sulfate glycosaminoglycans (GAGs). HS GAG accumulation and/or decreased HS GAG degradation is postulated to be the key initiating event. HS GAGs and highly sulfated macromolecules induce Aß 1-40 (but not 1-42) to form spherical congophilic maltese-cross star-like amyloid core deposits identical to those in the AD brain. Heparin/HS also induces tau protein to form paired helical filaments (PHFs). Increased sulfation and/or decreased degradation of HSPGs and HS GAGs that occur due to brain aging leads to the formation of plaques and tangles in AD brain. Knockout of HS genes markedly reduce the accumulation of Aß fibrils in the brain demonstrating that HS GAGs are key. Bacteria and viruses all use cell surface HS GAGs for entry into cells, including SARS-CoV-2. Bacteria and viruses cause HS GAGs to rapidly increase to cause near-immediate aggregation of Aß fibrils. "AD-in-a-dish" studies use "Matrigel" as the underlying scaffold that spontaneously causes plaque, and then tangle formation in a dish. Matrigel mostly contains large amounts of perlecan, the same specific HSPG implicated in AD and amyloid disorders. Mucopolysaccharidoses caused by lack of specific HS GAG enzymes lead to massive accumulation of HS in lysosomal compartments in neurons and contribute to cognitive impairment in children. Neurons full of HS demonstrate marked accumulation and fibrillization of Aß, tau, α-synuclein, and prion protein (PrP) in mucopolysaccharidosis animal models demonstrating that HS GAG accumulation is a precursor to Aß accumulation in neurons. Brain aging leads to changes in HSPGs, including newly identified splice variants leading to increased HS GAG sulfation in the AD brain. All of these events lead to the new "Unifying Hypothesis of Alzheimer's disease" that further implicates HSPGs /HS GAGs as key (as first hypothesized by Snow and Wight in 1989).

In vitro comparison of major memory-support dietary supplements for their effectiveness in reduction/inhibition of beta-amyloid protein fibrils and tau protein tangles: key primary targets for memory loss.

Memory loss is primarily caused by the accumulation of both brain plaques [(consisting of beta-amyloid protein (Aß) 1-42)] and neurofibrillary tangles (consisting of paired helical and straight filaments containing tau protein). Neuroinflammation is the third key and important factor that leads to accelerated memory loss and eventual dementia. Brain plaques, tangles and inflammation is the trilogy mainly responsible for causing memory loss that has now been documented for over 20 years in the scientific literature. The present investigation used in vitro quantitative methods to directly compare the ability of major memory-support dietary supplements to reduce pre-formed Aß 1-42 fibrils (21 supplements tested) and tau protein paired helical/straight filaments (13 supplements tested)-two of the three most important targets for memory loss. Additionally, 18 different manufacturers of cat's claw (Uncaria tomentosa) were directly compared for their ability to inhibit/reduce Aß 1-42 fibrils and/or tau paired helical/straight filaments based on recent findings that PTI-00703 cat's claw is a specific and potent inhibitor/reducer of all three targets -brain plaques, tangles and inflammation (Snow et al. in Sci Rep 9:561, 2019). In the present investigation quantitative Thioflavin T fluorometry was used on a comparative weight-to-weight basis at increasing concentrations with ingredients tested from the actual capsules the consumer ingests. Major memory-support dietary supplements were directly compared for their ability to inhibit and disaggregate/reduce both Aß 1-42 fibrils and/or tau paired helical/straight filaments. Dietary supplements touted to enhance memory comparatively tested included Prevagen, FOCUSfactor, PROCERA AVH, Alpha Brain, NAD+OVIM, BRAIN JUICE, Cebria, EXCELEROL, NOOCUBE, US Doctor's Clinical Brain Power ADVANCED, healthycell pro, LUMONOL, Brain Awake, BRAIN ARMOR, brainMD (BRAIN & MEMORY POWER BOOST), Brain Support, Clarity (BRAIN HEALTH FORMULA), brainMD (NEUROVITE PLUS), neuriva (Original and Plus) and percepta. This is the first paper to actually comparatively test these memory-support supplements for their ability to reduce Aß fibrils and tau protein tangles. Percepta (PTI-00703 cat's claw and a specific oolong tea extract) was determined to be the most effective and potent memory support dietary supplement to disaggregate/disrupt Aß 1-42 fibrils (range of 25-89%) and tau paired helical/straight filaments (range of 26-86%) at all 3-4 doses tested in comparison to other major memory-support dietary supplements tested. This was at least more than double (> 50%) for percepta reducing Aß 1-42 fibrils and in comparison to the other 20 memory-support dietary supplements tested. The ranking order for memory-support supplement effects based on reducing Aß 1-42 fibrils (Aß 1-42: memory-support supplement at 1:0.1 weight-to-weight in a 3-day study) was percepta (69.6% reduction) >>> Alpha Brain (34.9% reduction) = US Doctor's Clinical Brain Power ADVANCED (32.4%) = BRAIN JUICE (30.1%) = neuriva Plus (27%) = neuriva Original (27%) > NEUROVITE PLUS (22.9%) = NOOCUBE (19.9%) = EXCELEROL (17.3%) = healthycell pro (17.2%) > Prevagen (12.9%) > PROCERA AVH (6.5%) = FOCUSfactor (5.5%) > Cebria (0%) = Brain Awake (0%) = Brain Support (0%) = brainMD (BRAIN & MEMORY POWER BOOST) (0%) = NAD+OVIM (0%) = BRAIN ARMOR (0%) = LUMONOL (0%). The ranking order for memory support supplement effects on reducing tau paired helical/straight filaments (tau:memory supplement at 1:1 weight-to-weight at 3 days) was percepta (85.7% reduction) >>> neuriva Plus (57.9%) >> BRAIN JUICE (41.9%) = EXCELEROL (41.0%) = neuriva Original (38.4%) = US Doctor's Clinical Brain Power ADVANCED (38.3%) = healthycell pro (37.6%) >> Alpha Brain (27.9%) >> NOOCUBE (17.6%) >> FOCUSfactor (8.7%) > Cebria (3.6%) = PROCERA AVH (0%) = Prevagen (0%). Congo red staining, Thioflavin S fluorescence, circular dichroism (CD) spectroscopy and electron microscopy confirmed the positive results observed with the supplement percepta. CD spectroscopy demonstrated that percepta caused a marked inhibition of beta-sheet secondary folding of tau protein into paired helical filaments. PTI-00703 cat's claw (main ingredient in percepta) was also identified as the most potent cat's claw bark powder (Uncaria tomentosa) to reduce and inhibit Aß 1-42 fibrils and tau tangles in comparison to 17 other manufacturers of cat's claw extracts. Although there are thousands of brain memory-support dietary supplements in the marketplace today, none of them have been directly compared and analyzed for their ability to reduce and/or inhibit two major targets of memory loss i.e. Aß 1-42 fibrils and tau paired helical/straight filaments (major constituents of brain plaques and tangles). In our comparison studies, we show that percepta has the most potent ability to disaggregate/reduce Aß 1-42 fibrils and tau protein paired helical/straight filaments as demonstrated by a variety of methods most likely due to the specific polyphenol content in PTI-00703 cat's claw (i.e. polyphenols and proanthocyanidins) as we have previously shown (Snow et al. in Sci Rep 9:561, 2019). Memory-support dietary supplements tested that also contained polyphenols and/or cat's claw in their product demonstrated some Aß fibril and tau protein tangle reducing activity, but were much less effective than percepta. Percepta's main ingredient, PTI-00703 cat's claw, has previously been shown to reduce brain amyloid plaques and Aß 1-42/40 insoluble/soluble levels in brain (in plaque-producing transgenic mice) with marked concurrent memory improvements (shown by Morris water maze testing) (Snow et al. in Sci Rep 9:561, 2019). The present investigation further confirms that percepta is one of the best dietary supplements that causes a marked reduction and inhibition of Aß fibrils and tau tangle filaments -two important major targets for memory-support. In addition, PTI-00703 cat's claw was the most effective cat's claw (Uncaria tomentosa) ingredient for reducing /disaggregating and inhibiting Aß 1-42 fibrils and tau protein paired helical/straight filaments in comparison to 17 other manufacturers of cat's claw extracts tested.

Species distribution models throughout the invasion history of Palmer amaranth predict regions at risk of future invasion and reveal challenges with modeling rapidly shifting geographic ranges.

Palmer amaranth (Amaranthus palmeri) is an annual plant native to the desert Southwest of the United States and Mexico and has become invasive and caused large economic losses across much of the United States. In order to examine the temporal and spatial dynamics of past invasion, and to predict future invasion, we developed a broad array of species distribution models (SDMs). In particular, we constructed sequential SDMs throughout the invasion history and asked how well those predicted future invasion (1970 to present). We showed that invasion occurred from a restricted set of environments in the native range to a diverse set in the invaded range. Spatial autocorrelation analyses indicated that rapid range expansion was facilitated by stochastic, long-distance dispersal events. Regardless of SDM approach, all SDMs built using datasets from early in the invasion (1970-2010) performed poorly and failed to predict most of the current invaded range. Together, these results suggest that climate is unlikely to have influenced early stages of range expansion. SDMs that incorporated data from the most recent sampling (2011-2017) performed considerably better, predicted high suitability in regions that have recently become invaded, and identified mean annual temperature as a key factor limiting northward range expansion. Under future climates, models predicted both further northward range expansion and significantly increased suitability across large portions of the U.S. Overall, our results indicate significant challenges for SDMs of invasive species far from climate equilibrium. However, our models based on recent data make more robust predictions for northward range expansion of A. palmeri with climate change.

The Amazon rain forest plant Uncaria tomentosa (cat's claw) and its specific proanthocyanidin constituents are potent inhibitors and reducers of both brain plaques and tangles.

Brain aging and Alzheimer's disease both demonstrate the accumulation of beta-amyloid protein containing "plaques" and tau protein containing "tangles" that contribute to accelerated memory loss and cognitive decline. In the present investigation we identified a specific plant extract and its constituents as a potential alternative natural solution for preventing and reducing both brain "plaques and tangles". PTI-00703 cat's claw (Uncaria tomentosa from a specific Peruvian source), a specific and natural plant extract from the Amazon rain forest, was identified as a potent inhibitor and reducer of both beta-amyloid fibrils (the main component of "plaques") and tau protein paired helical filaments/fibrils (the main component of "tangles"). PTI-00703 cat's claw demonstrated both the ability to prevent formation/aggregation and disaggregate preformed Aß fibrils (1-42 and 1-40) and tau protein tangles/filaments. The disaggregation/dissolution of Aß fibrils occurred nearly instantly when PTI-00703 cat's claw and Aß fibrils were mixed together as shown by a variety of methods including Thioflavin T fluorometry, Congo red staining, Thioflavin S fluorescence and electron microscopy. Sophisticated structural elucidation studies identified the major fractions and specific constituents within PTI-00703 cat's claw responsible for both the observed "plaque" and "tangle" inhibitory and reducing activity. Specific proanthocyanidins (i.e. epicatechin dimers and variants thereof) are newly identified polyphenolic components within Uncaria tomentosa that possess both "plaque and tangle" reducing and inhibitory activity. One major identified specific polyphenol within PTI-00703 cat's claw was epicatechin-4ß-8-epicatechin (i.e. an epicatechin dimer known as proanthocyanidin B2) that markedly reduced brain plaque load and improved short-term memory in younger and older APP "plaque-producing" (TASD-41) transgenic mice (bearing London and Swedish mutations). Proanthocyanidin B2 was also a potent inhibitor of brain inflammation as shown by reduction in astrocytosis and gliosis in TASD-41 transgenic mice. Blood-brain-barrier studies in Sprague-Dawley rats and CD-1 mice indicated that the major components of PTI-00703 cat's claw crossed the blood-brain-barrier and entered the brain parenchyma within 2 minutes of being in the blood. The discovery of a natural plant extract from the Amazon rain forest plant (i.e. Uncaria tomentosa or cat's claw) as both a potent "plaque and tangle" inhibitor and disaggregator is postulated to represent a potential breakthrough for the natural treatment of both normal brain aging and Alzheimer's disease.

Whispering gallery modes in standard optical fibres for fibre profiling measurements and sensing of unlabelled chemical species.

Whispering gallery mode resonances in liquid droplets and microspheres have attracted considerable attention due to their potential uses in a range of sensing and technological applications. We describe a whispering gallery mode sensor in which standard optical fibre is used as the whispering gallery mode resonator. The sensor is characterised in terms of the response of the whispering gallery mode spectrum to changes in resonator size, refractive index of the surrounding medium, and temperature, and its measurement capabilities are demonstrated through application to high-precision fibre geometry profiling and the detection of unlabelled biochemical species. The prototype sensor is capable of detecting unlabelled biomolecular species in attomole quantities.