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Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

AbstractPrimary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Efficient removal of heterocyclic organosulfur compounds from fuels can relieve increasingly serious environmental problems (e.g., gas exhaust contaminants triggering the formation of acid rain that can damage fragile ecological systems). Toward this end, novel metal-organic frameworks (MOFs)-based sorbent materials are designed and synthesized with distinct hard and soft metal building units, specifically {[Yb6Cu12(OH)4(PyC)12(H2O)36]·(NO3)14·xS} n (QUST-81) and {[Yb4O(H2O)4Cu8(OH)8/3(PyC)8(HCOO)4]·(NO3)10/3·xS} n (QUST-82), where H2PyC = 4-Pyrazolecarboxylic acid. Exploiting the hard/soft duality, it is shown that the more stable QUST-82 can preserve desulfurization efficiency in the presence of competing nitrogen-containing contaminate. In addition, thermodynamically controlled single-crystal-to-single-crystal (SC-SC) phase transition is uncovered from QUST-81 to QUST-82, and in turn, mechanistic features are probed via X-ray diffraction, inductively coupled plasma atomic emission spectroscopy, and ab initio molecular dynamics simulations.

Robust modern gradients in sea surface temperature (SST) and biological productivity across the eastern equatorial Pacific (EEP) Ocean between 80° and 140°W derive from vigorous upwelling of cold and nutrient‐rich waters. However, during the mid‐Pliocene warm period (3.0–3.3 Ma), the zonal SST gradient within the EEP was reduced to <0.5°C while the productivity gradient remained as strong if not stronger than modern. We consider the oceanographic mechanisms and external climate forcings responsible for the evolution of the SST‐productivity coupling. We synthesize existing records and present new reconstructions of alkenone biomarker SST and productivity from four EEP sites. The progressive SST gradient strengthening over the Plio‐Pleistocene contrasted with the stronger Late Pliocene surface productivity gradient relative to modern. Dominance of the oceanic tunnel over surface forcings best explains these observations: SST changes reflect extratropical water masses cooling toward the present while productivity proxies suggest these waters became less nutrient‐rich. Plain Language Summary: The modern eastern tropical Pacific Ocean is cold and highly biologically productive because nutrients important to organisms at the base of the marine food web are brought from the colder deeper ocean to the sunlit zone. Therefore, cold waters found at the eastern margin of the equatorial Pacific are more productive than the central and western regions. However, during a globally warmer period 3 million years ago, warm waters in the eastern tropical Pacific supported higher productivity than in the recent past. We reconstructed the surface temperature and productivity from four sites in the eastern Pacific over the last 3 million years to assess how the temperature and productivity relationship evolved to the modern state. We proposed that changes in ocean temperature and nutrient conditions at the mid‐latitude origination of water emerging in the tropical Pacific influenced the evolving relationship between temperature and productivity as opposed to regional factors such as wind‐driven upwelling of deeper water. These connections between the poles and the tropics are important to consider as the oceans warm in the coming decades. Key Points: The modern tight coupling between ocean temperature and productivity in the eastern equatorial Pacific was weaker during the PlioceneModern east‐west temperature gradients developed by ∼1.7 Ma, but stronger than modern productivity gradients persisted through 400 kaTemperature gradient strengthening largely reflects progressively cooler but less nutrient‐rich water upwelling from extratropical regions [ABSTRACT FROM AUTHOR]

Purpose: Type 2 diabetes mellitus (T2DM) frequently presents with modified cardiometabolic risk profiles, indicative of an elevated susceptibility to cardiovascular disease (CVD). Cardiometabolic risk factors such as obesity, hyperglycemia, hypertension, insulin resistance and dyslipidemia are known contributors to increased CVD hazard in individuals with T2DM. This study evaluated the glycemic control-based cardiometabolic risk profiles of black Zimbabweans with T2DM. Patients and Methods: A cross-sectional study of 116 T2DM patients recruited from diabetic clinics at Parirenyatwa and Sally Mugabe Hospitals, Harare, Zimbabwe, was conducted. Blood samples were collected for glycated hemoglobin (HbA1c) and lipid profile assessment. The Framingham risk scores (FRS) based on body mass index (BMI) and lipid profile were used to determine CVD risk. Parametric variables were analyzed using one-way analysis of variance (ANOVA) with post hoc Bonferroni correction, while non-parametric variables were compared using the Kruskal–Wallis test with post hoc Dunn test for multiple comparisons. Results: The overall frequency of dyslipidemia was 83.6% (n=97) and hypoalphalipoproteinemia was the most prevalent dyslipidemia (79.3%). Median HDLC levels were significantly lower in participants with poor glycemic control (1.12 mmol/L) compared to those with good glycemic control group (1.37 mmol/L) (p=0.011). Despite lack of significant variations in Framingham Risk Scores, there was a trend towards lower FRS-BMI in the good control group (29.8%) compared to the inadequate control (35.4%) and poor control (32.7%) groups (p=0.078). Conclusion: Duration since DM diagnosis was observed to be an important risk factor for poor glycemic control being significantly shorter in those with good glycemic control compared to those with inadequate and poor control. Overall, there was no significant difference in HbA1c status by age but individuals with poor glycemic control were significantly older than those with good control. The most prevalent dyslipidemia among the study participants was hypoalphalipoproteinemia which is reportedly associated with genetic predisposition, warranting further investigations. [ABSTRACT FROM AUTHOR]

In the last decade, huanglongbing (HLB) has reduced production of Florida grapefruit by 75%, mandarin by 78% and sweet orange by 52%. This decrease is significant for the Indian River District, which produces approximately 80% of the total grapefruit crop grown in Florida (National Agricultural Statistics Service, 2021). Several strategies have been considered to keep citrus groves productive in HLB times. Rootstock field trials are cost-effective since vigorous, healthy rootstocks enhance disease tolerance of the scion and boost yields that increase growers’ profits.

Efficacy beliefs are the foundation of human agency. Beliefs influenced students’ motivation to learn. Students' self-efficacy beliefs could be improved as long as one has a clear idea about the sources of self-efficacy beliefs. Students enable them to grow as self-efficient individuals and overcome problems they face in educational stages or their future life if provided with the opportunity and training on self-efficacy beliefs. Hence, this paper describes the level of efficacy and degree of college readiness of senior high students of a Diocesan Catholic School in Antique during the School Year 2019-2020. Likewise, it explores the significant difference between students’ demographics, self-efficacy, and college readiness. Moreover, it determines the correlation between self-efficacy and college readiness of the students; and whether self-efficacy influenced college readiness.

ContextCyanide is a component of smoke in residential and industrial fires, and accidental exposure to cyanide occurs in a variety of industries. Moreover, cyanide has the potential to be used by terrorists, particularly in a closed space such as an airport or train station. Current therapies for cyanide poisoning must be given by intravenous administration, limiting their use in treating mass casualties.ObjectiveWe are developing two new cyanide antidotes--cobinamide, a vitamin B(12) analog, and sulfanegen, a 3-mercaptopyruvate prodrug. Both drugs can be given by intramuscular administration, and therefore could be used to treat a large number of people quickly. We now asked if the two drugs would have an augmented effect when combined.Materials and methodsWe used a non-lethal and two different lethal models of cyanide poisoning in mice. The non-lethal model assesses neurologic recovery by quantitatively evaluating the innate righting reflex time of a mouse. The two lethal models are a cyanide injection and a cyanide inhalation model.ResultsWe found that the two drugs are at least additive when used together in both the non-lethal and lethal models: at doses where all animals died with either drug alone, the combination yielded 80 and 40% survival in the injection and inhalation models, respectively. Similarly, drug doses that yielded 40% survival with either drug alone, yielded 80 and 100% survival in the injection and inhalation models, respectively. As part of the inhalation model, we developed a new paradigm in which animals are exposed to cyanide gas, injected intramuscularly with an antidote, and then re-exposed to cyanide gas. This simulates cyanide exposure of a large number of people in a closed space, because people would remain exposed to cyanide, even after receiving an antidote.ConclusionThe combination of cobinamide and sulfanegen shows great promise as a new approach to treating cyanide poisoning.

The aim of this study is to investigate the ability of intramuscular and intravenous sulfanegen sodium treatment to reverse cyanide effects in a rabbit model as a potential treatment for mass casualty resulting from cyanide exposure. Cyanide poisoning is a serious chemical threat from accidental or intentional exposures. Current cyanide exposure treatments, including direct binding agents, methemoglobin donors, and sulfur donors, have several limitations. Non-rhodanese mediated sulfur transferase pathways, including 3-mercaptopyruvate sulfurtransferase (3-MPST) catalyze the transfer of sulfur from 3-MP to cyanide, forming pyruvate and less toxic thiocyanate. We developed a water-soluble 3-MP prodrug, 3-mercaptopyruvatedithiane (sulfanegen sodium), with the potential to provide a continuous supply of substrate for CN detoxification. In addition to developing a mass casualty cyanide reversal agent, methods are needed to rapidly and reliably diagnose and monitor cyanide poisoning and reversal. We use non-invasive technology, diffuse optical spectroscopy (DOS) and continuous wave near infrared spectroscopy (CWNIRS) to monitor physiologic changes associated with cyanide exposure and reversal. A total of 35 animals were studied. Sulfanegen sodium was shown to reverse the effects of cyanide exposure on oxyhemoglobin and deoxyhemoglobin rapidly, significantly faster than control animals when administered by intravenous or intramuscular routes. RBC cyanide levels also returned to normal faster following both intramuscular and intravenous sulfanegen sodium treatment than controls. These studies demonstrate the clinical potential for the novel approach of supplying substrate for non-rhodanese mediated sulfur transferase pathways for cyanide detoxification. DOS and CWNIRS demonstrated their usefulness in optimizing the dose of sulfanegen sodium treatment.

There is a lack of knowledge on the histologic outcomes of loop electrosurgical excision procedure (LEEP) biopsies in the diagnosis, treatment, and prevention of cervical cancer in Zambia. This study determined the outcomes of LEEP biopsies and associated factors at a tertiary hospital. We conducted a retrospective chart review of patients evaluated at a tertiary hospital cervical cancer screening centre. From the database, we identified patients who underwent LEEP between January 2015 and June 2018. We extracted demographic data, HIV data, and LEEP biopsy results. A P value less than 0.05 was considered statistically significant. 137 charts were identified, and 114 were included in the final analysis. 23 were excluded for missing histology. The mean age of participants was 36.3 ± 9.6. Histology outcomes revealed that 37% had cervicitis, while CIN 1, 2, and 3 contributed to 27%, 14%, and 3%, respectively. Squamous cell cancer was present in 8% (age groups 35–49) and was three times higher (13%) in HIV-positive compared to HIV-negative participants (3.8%). Normal histology accounted for 11%. Increasing age (P=0.029), less than tertiary education (P=0.0011), and being married (P=0.017) increased the chances of having cancer in the chi-square analysis, while single women had lower odds of having CIN 1 (OR = 0.012) in the multinomial logistic regression. There is a need for increased cervical cancer screening and training in precancer treatment and holistic consideration of other factors like age in addition to the positive VIA test in advising patients on treatment options.

Abstract Efficient removal of heterocyclic organosulfur compounds from fuels can relieve increasingly serious environmental problems (e.g., gas exhaust contaminants triggering the formation of acid rain that can damage fragile ecological systems). Toward this end, novel metal‐organic frameworks (MOFs)‐based sorbent materials are designed and synthesized with distinct hard and soft metal building units, specifically {[Yb6Cu12(OH)4(PyC)12(H2O)36]·(NO3)14·xS}n (QUST‐81) and {[Yb4O(H2O)4Cu8(OH)8/3(PyC)8(HCOO)4]·(NO3)10/3·xS}n (QUST‐82), where H2PyC = 4‐Pyrazolecarboxylic acid. Exploiting the hard/soft duality, it is shown that the more stable QUST‐82 can preserve desulfurization efficiency in the presence of competing nitrogen‐containing contaminate. In addition, thermodynamically controlled single‐crystal‐to‐single‐crystal (SC–SC) phase transition is uncovered from QUST‐81 to QUST‐82, and in turn, mechanistic features are probed via X‐ray diffraction, inductively coupled plasma atomic emission spectroscopy, and ab initio molecular dynamics simulations.