Territory and population attributes affect Florida scrub-jay fecundity in fire-adapted ecosystems.

Fecundity, the number of young produced by a breeding pair during a breeding season, is a primary component in evolutionary and ecological theory and applications. Fecundity can be influenced by many environmental factors and requires long-term study due to the range of variation in ecosystem dynamics. Fecundity data often include a large proportion of zeros when many pairs fail to produce any young during a breeding season due to nest failure or when all young die independently after fledging. We conducted color banding and monthly censuses of Florida scrub-jays (Aphelocoma coerulescens) across 31 years, 15 populations, and 761 territories along central Florida's Atlantic coast. We quantified how fecundity (juveniles/pair-year) was influenced by habitat quality, presence/absence of nonbreeders, population density, breeder experience, and rainfall, with a zero-inflated Bayesian hierarchical model including both a Bernoulli (e.g., brood success) and a Poisson (counts of young) submodel, and random effects for year, population, and territory. The results identified the importance of increasing "strong" quality habitat, which was a mid-successional state related to fire frequency and extent, because strong territories, and the proportion of strong territories in the overall population, influenced fecundity of breeding pairs. Populations subject to supplementary feeding also had greater fecundity. Territory size, population density, breeder experience, and rainfall surprisingly had no or small effects. Different mechanisms appeared to cause annual variation in fecundity, as estimates of random effects were not correlated between the success and count submodels. The increased fecundity for pairs with nonbreeders, compared to pairs without, identified empirical research needed to understand how the proportion of low-quality habitats influences population recovery and sustainability, because dispersal into low-quality habitats can drain nonbreeders from strong territories and decrease overall fecundity. We also describe how long-term study resulted in reversals in our understanding because of complications involving habitat quality, sociobiology, and population density.

The John S. Najarian symposium: The past, present, and future of surgery and transplantation, May 20, 2022, Minneapolis, MN.

Dr John S Najarian (1927-2020), chairman of the Department of Surgery at the University of Minnesota from 1967 to 1993, was a pioneer in surgery, clinical immunology and transplantation. A Covid-delayed Festschrift was held in his honor on May 20, 2022. The speakers reflected on his myriad contributions to surgery, transplantation, and resident/fellow training, as well as current areas of ongoing research to improve clinical outcomes. Of note, Dr Najarian was a founder of the journal Clinical Transplantation.

Mechanistic evidence and exercise interventions: Causal claims, extrapolation, and implementation.

RATIONALE: Exercise interventions and policies are widely prescribed in both sport and healthcare. Research investigating exercise interventions and policies is generally conducted using an Evidence-Based framework, placing an emphasis on evidence gathered from randomised controlled trials (RCTs). AIMS AND OBJECTIVES: To explore the idea that, in addition to the assessment of evidence from RCTs when investigating exercise interventions, mechanistic studies ought to also be assessed and considered. METHODS: This article assesses the rationale supporting the use of RCTs as evidence for exercise interventions, and the use of evidence of mechanisms in establishing efficacy, determining external validity, and tailoring interventions. RESULTS AND CONCLUSIONS: The article argues that evidence from mechanistic studies ought to be considered alongside evidence from RCTs because: as RCTs investigating exercise interventions tend to be of low quality, mechanistic studies ought to be used to reinforce the evidence base; further, evidence from mechanistic studies is highly useful for both questions of extrapolation and implementation. This article argues for this on theoretical grounds, and also draws on a number of case studies.

Raman spectroscopy enables phenotyping and assessment of nutrition values of plants: a review.

Our civilization has to enhance food production to feed world's expected population of 9.7 billion by 2050. These food demands can be met by implementation of innovative technologies in agriculture. This transformative agricultural concept, also known as digital farming, aims to maximize the crop yield without an increase in the field footprint while simultaneously minimizing environmental impact of farming. There is a growing body of evidence that Raman spectroscopy, a non-invasive, non-destructive, and laser-based analytical approach, can be used to: (i) detect plant diseases, (ii) abiotic stresses, and (iii) enable label-free phenotyping and digital selection of plants in breeding programs. In this review, we critically discuss the most recent reports on the use of Raman spectroscopy for confirmatory identification of plant species and their varieties, as well as Raman-based analysis of the nutrition value of seeds. We show that high selectivity and specificity of Raman makes this technique ideal for optical surveillance of fields, which can be used to improve agriculture around the world. We also discuss potential advances in synergetic use of RS and already established imaging and molecular techniques. This combinatorial approach can be used to reduce associated time and cost, as well as enhance the accuracy of diagnostics of biotic and abiotic stresses.

Raman Spectroscopy Can Distinguish Glyphosate-Susceptible and -Resistant Palmer Amaranth (Amaranthus palmeri).

The non-judicious use of herbicides has led to a widespread evolution of herbicide resistance in various weed species including Palmer amaranth, one of the most aggressive and troublesome weeds in the United States. Early detection of herbicide resistance in weed populations may help growers devise alternative management strategies before resistance spreads throughout the field. In this study, Raman spectroscopy was utilized as a rapid, non-destructive diagnostic tool to distinguish between three different glyphosate-resistant and four -susceptible Palmer amaranth populations. The glyphosate-resistant populations used in this study were 11-, 32-, and 36-fold more resistant compared to the susceptible standard. The 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene copy number for these resistant populations ranged from 86 to 116. We found that Raman spectroscopy could be used to differentiate herbicide-treated and non-treated susceptible populations based on changes in the intensity of vibrational bands at 1156, 1186, and 1525 cm-1 that originate from carotenoids. The partial least squares discriminant analysis (PLS-DA) model indicated that within 1 day of glyphosate treatment (D1), the average accuracy of detecting herbicide-treated and non-treated susceptible populations was 90 and 73.3%, respectively. We also found that glyphosate-resistant and -susceptible populations of Palmer amaranth can be easily detected with an accuracy of 84.7 and 71.9%, respectively, as early as D1. There were relative differences in the concentration of carotenoids in plants with different resistance levels, but these changes were not significant. The results of the study illustrate the utility of Raman spectra for evaluation of herbicide resistance and stress response in plants under field conditions.

An Evaluation of the Use of Aggressive Fluid Resuscitation in the Early Treatment of Sepsis Patients.

Introduction Fluid resuscitation is a critical aspect of the sepsis protocol with the usual initial dose being 30 mL per kilogram. Although this dose is well accepted in patients with normal cardiac function, there is some significant variation in clinical practice concerning the optimal fluid resuscitation in septic patients with underlying congestive heart failure (CHF). Many different approaches have been tried to best treat these patients by using lesser volumes of fluid. The purpose of this retrospective study is to attempt to better define optimal fluid resuscitation in congestive heart failure patients and whether standard fluid resuscitation exacerbates CHF in these cases. Methods This was a retrospective study involving patients admitted to the Emergency Department (ED) during the time period of September of 2016 through March of 2019 with a primary diagnosis of sepsis and pre-existing CHF. Data collected from the data warehouse and patient charts included demographics, total amount of fluid received in the ED and outcome data. Evidence of fluid overload (chest X-ray [CXR] evidence, rising B-type natriuretic peptide [BNP], or use of diuretics), was evaluated with respect to in-hospital mortality, white blood cell (WBC) count and comorbidities (chronic obstructive pulmonary disease [COPD], hypertension and coronary artery disease). Results There were 422 patients included in the cohort. Of the 422, 113 (26.8%) patients showed evidence of fluid overload on CXR during hospital stay and received diuretics and therefore considered in the CHF exacerbation group. The patients that experienced CHF exacerbation were significantly older (mean ± SD, 70.9 ± 11.8 years versus 67.4 ± 15.1 years, p=0.014). Patients with exacerbation also received more fluid (median and interquartile range, 3.0, 2:5.5 L versus 2.0, 1:4.3 L, p=0.017). The receiver operating characteristic curve analysis for fluid to predict exacerbation resulted in an area under the curve of 0.59 with a 95% confidence interval (CI) of 0.52 to 0.65, p=0.012. The Youden Index was used to determine an optimal cutoff value of 2.6 L. The percentage of patients in the exacerbation group above the threshold was significantly higher (57.3%) than those without exacerbation (43.3%), p=0.019. Following multivariate analysis, age greater than 60 (odds ratio [OR]: 2.5; CI: 1.4-4.6, p=0.003) and fluid cutoff of 2.6 L (OR: 1.9; CI: 1.2-3.1, p=0.007) were both found to be independent predictors of CHF exacerbation. There was no significant difference in mortality based on the total fluid received in the ED. Conclusion The findings of this study showed that septic patients with pre-existing CHF who received more than 2.6 L of fluid in the ED were 90% more likely to develop symptoms of CHF exacerbation with no evidence of lowering mortality compared to the group that received less than 2.6 L. Our data supports the practice of limiting total fluid resuscitation in CHF to 2.6 L and reconfirms the idea that fluid resuscitation for patients with CHF needs to be individualized.

Impact of WIN site inhibitor on the WDR5 interactome.

The chromatin-associated protein WDR5 is a promising pharmacological target in cancer, with most drug discovery efforts directed against an arginine-binding cavity in WDR5 called the WIN site. Despite a clear expectation that WIN site inhibitors will alter the repertoire of WDR5 interaction partners, their impact on the WDR5 interactome remains unknown. Here, we use quantitative proteomics to delineate how the WDR5 interactome is changed by WIN site inhibition. We show that the WIN site inhibitor alters the interaction of WDR5 with dozens of proteins, including those linked to phosphatidylinositol 3-kinase (PI3K) signaling. As proof of concept, we demonstrate that the master kinase PDPK1 is a bona fide high-affinity WIN site binding protein that engages WDR5 to modulate transcription of genes expressed in the G2 phase of the cell cycle. This dataset expands our understanding of WDR5 and serves as a resource for deciphering the action of WIN site inhibitors.

A Proof-of-Principle Study of Non-invasive Identification of Peanut Genotypes and Nematode Resistance Using Raman Spectroscopy.

Identification of peanut cultivars for distinct phenotypic or genotypic traits whether using visual characterization or laboratory analysis requires substantial expertise, time, and resources. A less subjective and more precise method is needed for identification of peanut germplasm throughout the value chain. In this proof-of-principle study, the accuracy of Raman spectroscopy (RS), a non-invasive, non-destructive technique, in peanut phenotyping and identification is explored. We show that RS can be used for highly accurate peanut phenotyping via surface scans of peanut leaves and the resulting chemometric analysis: On average 94% accuracy in identification of peanut cultivars and breeding lines was achieved. Our results also suggest that RS can be used for highly accurate determination of nematode resistance and susceptibility of those breeding lines and cultivars. Specifically, nematode-resistant peanut cultivars can be identified with 92% accuracy, whereas susceptible breeding lines were identified with 81% accuracy. Finally, RS revealed substantial differences in biochemical composition between resistant and susceptible peanut cultivars. We found that resistant cultivars exhibit substantially higher carotenoid content compared to the susceptible breeding lines. The results of this study show that RS can be used for quick, accurate, and non-invasive identification of genotype, nematode resistance, and nutrient content. Armed with this knowledge, the peanut industry can utilize Raman spectroscopy for expedited breeding to increase yields, nutrition, and maintaining purity levels of cultivars following release.

Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design.

The frequent deregulation of MYC and its elevated expression via multiple mechanisms drives cells to a tumorigenic state. Indeed, MYC is overexpressed in up to ∼50% of human cancers and is considered a highly validated anticancer target. Recently, we discovered that WD repeat-containing protein 5 (WDR5) binds to MYC and is a critical cofactor required for the recruitment of MYC to its target genes and reported the first small molecule inhibitors of the WDR5-MYC interaction using structure-based design. These compounds display high binding affinity, but have poor physicochemical properties and are hence not suitable for in vivo studies. Herein, we conducted an NMR-based fragment screening to identify additional chemical matter and, using a structure-based approach, we merged a fragment hit with the previously reported sulfonamide series. Compounds in this series can disrupt the WDR5-MYC interaction in cells, and as a consequence, we observed a reduction of MYC localization to chromatin.

Structural Elucidation of Peptide Binding to KLHL-12, a Substrate Specific Adapter Protein in a Cul3-Ring E3 Ligase Complex.

KLHL-12 is a substrate specific adapter protein for a Cul3-Ring ligase complex. It is a member of the Kelch ß-propeller domain subclass of Cullin-Ring substrate recognition domains. This E3 ubiquitin ligase complex has many activities, including acting as a negative regulator of the Wnt signaling pathway by mediating ubiquitination and subsequent proteolysis of Dvl3/Dsh3. KLHL-12 is also known to mediate the polyubiquitination of the dopamine D4 receptor (D4.2), the ubiquitination of KHSRP, a protein that is involved in IRES translation, and also the ubiquitination of Sec31, which is involved in endoplasmic reticulum-Golgi transport by regulating the size of COPII coats. Earlier studies broadly defined the substrate binding regions for D4.2 and Dvl3/Dsh3 to KLHL-12. We tested several peptides from these regions and succeeded in identifying a short peptide that bound to KLHL-12 with low micromolar affinity. To better understand the sequence specificity of this peptide, we used alanine substitutions to map the important residues and obtained an X-ray structure of this peptide bound to KLHL-12. This structure and our peptide affinity measurements suggest a sequence motif for peptides that bind to the top face of KLHL-12. Understanding this binding site on KLHL-12 may contribute to efforts to find small molecule ligands that can either directly inhibit the degradation of substrate proteins or be used in targeted protein degradation strategies using PROTACs.

Raman-Based Diagnostics of Biotic and Abiotic Stresses in Plants. A Review.

Digital farming is a novel agricultural philosophy that aims to maximize a crop yield with the minimal environmental impact. Digital farming requires the development of technologies that can work directly in the field providing information about a plant health. Raman spectroscopy (RS) is an emerging analytical technique that can be used for non-invasive, non-destructive, and confirmatory diagnostics of diseases, as well as the nutrient deficiencies in plants. RS is also capable of probing nutritional content of grains, as well as highly accurate identification plant species and their varieties. This allows for Raman-based phenotyping and digital selection of plants. These pieces of evidence suggest that RS can be used for chemical-free surveillance of plant health directly in the field. High selectivity and specificity of this technique show that RS may transform the agriculture in the US. This review critically discusses the most recent research articles that demonstrate the use of RS in diagnostics of abiotic and abiotic stresses in plants, as well as the identification of plant species and their nutritional analysis.

Visible light as an inhibitor of Campylobacter jejuni.

INTRODUCTION: Campylobacter jejuni is a Gram-negative, microaerophilic bacteria that is the leading cause of food-borne illnesses in the United States; it frequently causes severe diarrhoea. Campylobacter jejuni has recently demonstrated antibiotic resistance; therefore, alternative methods for treating these infections must be investigated. Visible light has proven to be an effective inhibitory agent for many medically significant species of bacteria and fungi. METHODS: Visible light in the blue range (405 nm and 464 nm) was administered to a suspension of Campylobacter jejuni. Brain-heart infusion agar was inoculated with the suspension of the organism following exposure to blue light at a dose of 24 Jcm2 for each wavelength. Inoculated plates were placed into a traditional Campy jar in order to mimic a 5% O2 atmosphere and incubated at 37 °C for 48 hours. Following incubation, colony forming units were counted and compared with controls to determine if the light energy had effectively inhibited the growth of the organism. RESULTS: Both 405 nm and 464 nm light at a dose of 24 Jcm2 were shown to be effective inhibitors of Campylobacter jejuni, with kill rates ranging from 82.4-98.9%. CONCLUSION: Blue light effectively inhibits Campylobacter jejuni.

Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.

WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.

Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction.

The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.

ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors.

The enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential therapeutic target for multiple myeloma. Malignant plasma cells produce and secrete large amounts of monoclonal protein, and inhibition of GGDPS results in disruption of protein geranylgeranylation which in turn impairs intracellular protein trafficking. Our previous work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. To explore the possibility of selective delivery of such compounds to plasma cells, new analogues with an ω-hydroxy group have been synthesized and examined for their enzymatic and cellular activity. These studies demonstrate that incorporation of the ω-hydroxy group minimally impairs GGDPS inhibitory activity. Furthermore conjugation of one of the novel ω-hydroxy GGDPS inhibitors to hyaluronic acid resulted in enhanced cellular activity. These results will allow future studies to focus on the in vivo biodistribution of HA-conjugated GGDPS inhibitors.

Mutations in Both the Surface and Transmembrane Envelope Glycoproteins of the RAV-2 Subgroup B Avian Sarcoma and Leukosis Virus Are Required to Escape the Antiviral Effect of a Secreted Form of the TvbS3 Receptor †.

The subgroup A through E avian sarcoma and leukosis viruses ASLV(A) through ASLV(E) are a group of highly related alpharetroviruses that have evolved to use very different host protein families as receptors. We have exploited genetic selection strategies to force the replication-competent ASLVs to naturally evolve and acquire mutations to escape the pressure on virus entry and yield a functional replicating virus. In this study, evolutionary pressure was exerted on ASLV(B) virus entry and replication using a secreted for of its Tvb receptor. As expected, mutations in the ASLV(B) surface glycoprotein hypervariable regions were selected that knocked out the ability for the mutant glycoprotein to bind the sTvbS3-IgG inhibitor. However, the subgroup B Rous associated virus 2 (RAV-2) also required additional mutations in the C-terminal end of the SU glycoprotein and multiple regions of TM highlighting the importance of the entire viral envelope glycoprotein trimer structure to mediate the entry process efficiently. These mutations altered the normal two-step ASLV membrane fusion process to enable infection.

Microporous polysaccharide hemosphere efficacy and safety in primary total knee arthroplasty.

Absorbable hemostats such as microporous polysaccharide hemospheres (MPH) are used to manage hemostasis and prevent complications in total knee arthroplasty (TKA). We aimed to determine safety and effectiveness of MPH use in TKA. Records were reviewed for blood loss, hematomas, and infections. No differences existed regarding demographics, superficial infections (P = 0.933) or hematomas (P = 0.393). Positive correlation existed between hematoma and superficial infection (P = 0.009). Blood loss was greater in the treatment group (P = 0.014). MPH demonstrated inferior bleeding control and had no effect on complications. Our results suggest application of this agent may be unnecessary.

Early diagnosis of femoral neck stress fractures may decrease incidence of bilateral progression and surgical interventions: A case report and literature review.

INTRODUCTION: Early intervention in femoral neck stress fractures (FNSFs) can be self- limiting, but they have an insidious presentation. High index of suspicion for an occult fracture is necessary to avoid bilateral progression and/or operative interventions. CASE PRESENTATION: A 83-year-old female, non-athlete, presents with multiple comorbidities and progressive bilateral FNSFs. Initially the patient presented with groin pain and radiographs demonstrated a non-displaced compression type fracture of the right femoral neck without any inciting events. Subsequently, during a post-operative visit of her right hip, a work-up for new onset contralateral groin pain revealed a non-displaced tension type fracture on the left femoral neck. Both FNSFs were treated with percutaneous cannulated screw fixation. DISCUSSION: Vitamin D deficiency, poor nutrition, and osteoporosis have been associated with developing stress fractures. This presents an interesting question of whether these frequently referenced risk factors play an interrelated role. Treatment algorithms are controversial, but have been successful in preventing the progression of occult stress fractures. Yet, identification of FNSFs represents a major challenge in diagnosis for clinicians. CONCLUSION: This case report documents an uncommon fracture pattern in the elderly population. With an aging population, it is pertinent to avoid missed opportunities for prompt diagnosis and implementation of noninvasive methods of treatment. Therefore, paying attention to the risk factors with a high index of suspicion would be ideal.