Rare Tautomers of Artificially Expanded Genetic Letters and their Effects on the Base Pair Stabilities.

In order to expand the existing genetic letters, it is necessary to design robust nucleotides that can function naturally in living cells. Therefore, it is desirable to examine the roles of recently-proposed second-generation artificially genetic letters in producing stable duplex DNA. Herein, a reliable dispersion-corrected density functional theory method is used to shed light on the electronic structures and properties of different rare tautomers of proposed expanded genetic letters and their effects on the base pair stabilities in the duplex DNA. It is found that the rare tautomers are not only stable in the aqueous medium but can also pair with natural bases to produce stable mispairs. Except for J and V, all of the artificial genetic letters are found to produce mispairs that are about 1-7 kcal mol-1 more stable than their complementary counterparts. They are also appreciably more stable than the naturally occurring G : C, A : T, and G : T pairs. Mainly attractive electrostatic interactions and polarity of the monomers are responsible for the higher base pair stabilities.

Posttraumatic stress disorder symptom severity is associated with reduced Montreal Cognitive Assessment scores in a sample of Vietnam War Veterans.

The goal of the present study was to examine associations between posttraumatic stress disorder (PTSD) symptom severity, the number of stressors experienced, and cognitive outcomes in a sample of U.S. Vietnam War Veterans (N = 274). Adults between 60 and 85 years of age completed a Vietnam Veterans Alzheimer's Disease Neuroimaging Initiative Project visit. A modified version of the Life Stressor Checklist-Revised (LSC-R) was used to assess the number of stressful experiences participants experienced, current PTSD severity scores were measured via the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV), and cognition was assessed using the Montreal Cognitive Assessment (MoCA). Linear regressions were conducted to examine the effect of CAPS-IV and LSC-R scores on cognitive performance. Higher CAPS-IV scores were associated with worse cognitive outcomes on the MoCA, ΔF(1, 264) = 12.686, p < .001, R2 = .142. In contrast, the number of reported stressful experiences was not associated with cognitive outcomes. After accounting for multiple comparisons, findings indicated that CAPS-IV severity scores were significantly associated with the MoCA memory index. In a sample of older Veterans, PTSD symptom severity, but not the number of reported stressors, was associated with poorer performance on a well-established cognitive function screening tool. Analyses of specific MoCA domains indicated that memory may be driving this association. These findings suggest that highly arousing stressors characteristic of PTSD, rather than stressful experiences more broadly, contribute to this association. Future work can use these findings to explore whether treating PTSD symptoms may help maintain cognitive function during the aging process.

Racial disparities in COVID-19 hospitalizations do not lead to disparities in outcomes.

OBJECTIVES: The objective of the study is the identification of racial differences in characteristics and comorbidities in patients hospitalized for COVID-19 and the impact on outcomes. STUDY DESIGN: The study design is a retrospective observational study. METHODS: Data for all patients admitted to seven community hospitals in Michigan, United States, with polymerase chain reaction confirmed diagnosis of COVID-19 from March 10 to April 15, 2020 were analyzed. The primary outcomes of racial disparity in inpatient mortality and intubation were analyzed using descriptive statistics and multivariate regression models. RESULTS: The study included 336 Black and 408 White patients. Black patients were younger (62.9 ± 15.0 years vs 71.8 ± 16.4, P < .001), had a higher mean body mass index (32.4 ± 8.6 kg/m2 vs 28.8 ± 7.5, P < .001), had higher prevalence of diabetes (136/336 vs 130/408, P = .02), and presented later (6.6 ± 5.3 days after symptom onset vs. 5.4 ± 5.4, P = .006) compared with White patients. Younger Black patients had a higher prevalence of obesity (age <65 years, 69.9%) than older Black patients (age >65 years, 39.2%) and younger White patients (age < 65, 55.1%). Intubation did not reach statistical significance for racial difference (Black patients 61/335 vs. 54/406, P = .08). Mortality was not higher in Black patients (65/335 vs. 142/406 in White patients, odds ratio 0.61, 95% confidence interval: 0.37 to 0.99, 2-sided P = .05) in multivariate analysis, accounting for other risk factors associated with mortality. CONCLUSIONS: Higher prevalence of obesity and diabetes in young Black populations may be the critical factor driving disproportionate COVID-19 hospitalizations in Black populations. Hospitalized Black patients do not have worse outcomes compared with White patients.

Role of different tautomers in the base-pairing abilities of some of the vital antiviral drugs used against COVID-19.

Repurposed drugs are now considered as attractive therapeutics against COVID-19. It is shown that Remdesivir, a nucleoside drug that was originally invented for the Ebola virus, is effective in suppressing the replication of SARS-CoV-2 that causes COVID-19. Similarly, Galidesivir, Favipiravir, Ribavirin, N4-hydroxycytidine (EIDD-1931), and EIDD-2801 (a prodrug of EIDD-1931) were also found to be effective against COVID-19. However, the mechanisms of action of these drugs are not yet fully understood. For example, in some experimental studies, these drugs were proposed to act as a RNA-chain terminator, while in other studies, these were proposed to induce base-pair mutations above the error catastrophe limit to stall the replication of the viral RNA. To understand the mutagenic effects of these drugs, the role of different tautomers in their base-pairing abilities is studied here in detail by employing a reliable dispersion-corrected density functional theoretic method. It is found that Remdesivir and Galidesivir can adopt both amino and imino tautomeric conformations to base-pair with RNA bases. While the insertions of G and U are preferred against the amino tautomers of these drugs, the insertion of C is mainly possible against the imino tautomers. However, although Favipiravir and Ribavirin can make stable base pair interactions by using their keto and enol tautomers, the formation of the latter pairs would be less probable due to the endothermic nature of the products. Interestingly, the insertions of all of the RNA bases are found to be possible against the keto tautomer of Favipiravir, while the keto tautomer of Ribavirin has a clear preference for G. Remarkably, due to the negligible difference in the stability of EIDD-2801 and EIDD-1931, these tautomers would coexist in the biological environment. The insertion of G is found to be preferred against EIDD-1931 and the incorporations of U, A, and G are preferred opposite EIDD-2801. These findings suggest that base-pair mutations are the main causes of the antiviral properties of these drugs.

Electron and hole interactions with P, Z, and P:Z and the formation of mutagenic products by proton transfer reactions.

P and Z have recently been identified as promiscuous artificial nucleobases, which can behave as G and C, respectively, in duplex DNA. These nucleobases have been shown to participate in the replication reaction and can form stable B-DNA. A short sequence of DNA containing P and Z has also been shown to help in the diagnosis of diseases. However, the behavior of P and Z exposed to radiation has not been explored. As electrons and holes are created during the interaction of radiation with DNA bases, it is desirable to understand the electron or hole trapping abilities of P and Z in duplex DNA. To unravel these abilities, electron affinities (EAs) and ionization potentials (IPs) of P and Z in bare and microhydrated complexes are computed and compared with those of G and C by using the B3LYP-D3 dispersion-corrected density functional theory method and the IEFPCM method to account for the bulk solvation in water. The computed EA and IP values of P and Z are found to be largely positive and hence their anions (P˙- and Z˙-) and cations (P˙+ and Z˙+) would be stable in DNA. It is further found that the electron trapping ability of Z is significantly higher than that of P, G, and C. However, the hole trapping ability of P is slightly higher than that of Z, but less than that of G. To account for the proton transfer abilities of Z, Z˙+, and Z˙-, the stabilities of different proton transferred products and their tautomers are also explored. It is found that among the different products, the one formed by the transfer of the N3 proton would be the most stable. However, the N3 proton transfer from Z to P in the P:Z and P:Z˙- complexes would be unfeasible due to the high barrier and endothermic nature of the reaction. Remarkably, the same reaction in the P:Z˙+ complex is found to be exothermic with a low barrier energy. Hence, the conversion of Z to Z˙+ would facilitate N3 proton transfer from Z to P in the P:Z complex. As the proton transferred products were suggested to induce genetic mutations, we propose that the formations of Z(N3 - H)˙ and P(N1 + H)+ in DNA would be mutagenic. These results are expected to help in the understanding of the radiation biology of P and Z in single-stranded and double-stranded DNA.

Novel small molecule IL-6 inhibitor suppresses autoreactive Th17 development and promotes Treg development.

Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in the United States in young adults, but current treatments are only partially effective, making it necessary to develop new, innovative therapeutic strategies. Myelin-specific interleukin (IL)-17-producing T helper type 17 (Th17) cells are a major subset of CD4 T effector cells (Teff ) that play a critical role in mediating the development and progression of MS and its mouse model, experimental autoimmune encephalomyelitis (EAE), while regulatory T cells (Treg ) CD4 T cells are beneficial for suppressing disease. The IL-6/signal transducer and activator of transcription 3 (STAT-3) signaling pathway is a key regulator of Th17 and Treg cells by promoting Th17 development and suppressing Treg development. Here we show that three novel small molecule IL-6 inhibitors, madindoline-5 (MDL-5), MDL-16 and MDL-101, significantly suppress IL-17 production in myelin-specific CD4 T cells in a dose-dependent manner in vitro. MDL-101 showed superior potency in suppressing IL-17 production compared to MDL-5 and MDL-16. Treatment of myelin-specific CD4 T cells with MDL-101 in vitro reduced their encephalitogenic potential following their subsequent adoptive transfer. Furthermore, MDL-101 significantly suppressed proliferation and IL-17 production of anti-CD3-activated effector/memory CD45RO+ CD4+ human CD4 T cells and promoted human Treg development. Together, these data demonstrate that these novel small molecule IL-6 inhibitors have the potential to shift the Teff  : Treg balance, which may provide a novel therapeutic strategy for ameliorating disease progression in MS.

Conformational stabilities of iminoallantoin and its base pairs in DNA: implications for mutagenicity.

The types of mutations induced by oxidatively damaged products of DNA are continuously in debate. For example, some biochemical studies have proposed that guanidinohydantoin (Gh) would induce exclusively G to C mutations, while other studies have predicted a mixture of various mutations including G to C, G to T and G to A. In addition to the nature of mutations, the exact reasons of these mutations are also not properly understood. It is suggested that Gh can easily isomerize to iminoallantoin (Ia) in a pH-dependent manner and the transition becomes complete at pH > 8. In order to understand Gh/Ia-induced mutations, we have here studied the role of the most stable tautomer of Ia in the R- and S-enantiomeric configurations in promoting mismatch base pair complexes in DNA by employing a density functional theoretical (DFT) approach. It is found that Ia can have 39 different possible tautomeric forms each in the R- and S-enantiomeric configurations, out of which the most stable tautomer would involve the deprotonation of the N1 atom and protonation of the N3 atom. The most stable tautomer of Ia can adopt three different rotameric conformations (Ia1, Ia2, and Ia3) of comparable stabilities. It is further revealed that these rotamers of Ia can interact with different bases of DNA in 88 different possible ways. However, the interaction of G with Ia3 in both the anti- and syn-conformations would be the most stable. It is further revealed that the base pairing patterns, binding energies and electronic environments of anti-Ia3:G and G:T complexes are similar. In addition to this, it is also found that the binding patterns and energies of Gh1:G and Ia3:G complexes are similar. Based on these results, it is proposed that under physiological conditions, Gh1 may be responsible for the observed G to C mutations in DNA, while in an acidic environment Ia3 may be responsible for the same mutations. This study has led to a solid foundation for further high resolution structural studies to completely unravel Ia-induced mutagenicity in DNA.

The R- and S-diastereoisomeric effects on the guanidinohydantoin-induced mutations in DNA.

Direct and indirect oxidation of guanine in DNA produces guanidinohydantoin (Gh), which is capable of inhibiting replication and inducing mutations during cellular activities. Although some biochemical studies have proposed that Gh may induce exclusively G to C mutations in DNA, other studies have predicted the occurrence of both G to C and G to T mutations. However, the exact reasons for these mutations and the dubious character of Gh in this context are not yet understood. Further, due to insufficient structural data, the electronic structure of Gh that can participate in the formation of different base pair complexes in DNA is also not known. Here, density functional theory (DFT) is used to find the most stable tautomers of Gh at the base level out of a total 112 possible tautomers and their involvement in mutagenesis is investigated by computing structures, energies and electronic properties of different base pair complexes formed between the syn- and anti-conformations of the most stable tautomer of Gh (aGh) and all the bases of DNA. It is found that aGh can coexist in R- and S-diastereoisomeric configurations. Due to the flexible guanidinium group, it can rotate about the N3-C4 bond in each of the above diastereoisomers to form two different stable conformations (aGh1 and aGh2). It is further shown that among the different base pair complexes involving aGh1, syn-aGh1:G is the most stable. This indicates that G would be easily incorporated against syn-aGh1 giving rise to G to C mutations in DNA. However, in the case of aGh2, G is the preferred base pair partner of syn-aGh2 and T is the preferred base pair partner of anti-aGh2. This implies that in addition to G to C mutations, the occurrence of aGh2 in DNA may also induce G to A mutations. Further, due to similarities between base pairing patterns and binding energies of syn-aGh1:A and syn-aGh2:A complexes with those of the T:A complex, DNA polymerases may mistakenly insert A opposite aGh1 or aGh2 by misrecognizing the latter as T. This may ultimately induce G to T mutations in DNA. However, as the constraints imposed by the DNA backbones and stacking interactions were not considered here, the possibilities of aGh2:T and aGh2:A base pairs need to be investigated experimentally. It is further found that the mutagenic character of aGh in the R- and S-diastereoisomeric forms is similar.

Binding of Nucleotide Inhibitors to the NS5 RdRp of the ZIKA Virus in the Replication Initiation State.

INTRODUCTION: The bindings of several ribonucleoside triphosphate (NTP) inhibitors to the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) are studied herein to identify potential drug-like candidates that can inhibit the replication of the viral genome by RdRp. METHOD: In this study, a guanosine triphosphate (GTP) bound RdRp structure is generated to model the replication initiation state of RdRp. Subsequently, the bindings of 30 NTP inhibitors to the GTP binding site of RdRp are studied in detail by using the molecular docking method. Based on the docking scores, four NTP inhibitors, such as 2'-Cmethyl- adenosine-5'-triphosphate (mATP), 7-deaza-2'-C-methyladenosine-TP (daza-- mATP), 1-N6-Ethenoadenosine-5'-triphosphate (eATP), and Remdesivir-5'-triphosphate (RTP) are shortlisted for further analysis by employing molecular dynamics simulations and binding free-energy methods. RESULTS: These inhibitors are found to bind to RdRp quite strongly, as evident from their relative binding free energies that lie between -31.54±4.54 to -89.46±4.58 kcal/- mol. As the binding of RTP to the GTP site of RdRp generates the most stable complex, which is about 45 kcal/mol more stable than the binding of GTP to RdRp, it is most likely that RTP may inhibit the replication of the Zika viral genome efficiently. CONCLUSION: However, experimental studies are required to measure the potency of RTP and other drugs before their clinical use.

Higher Cerebrospinal Fluid Levels of Amyloid-ß40 Following Traumatic Brain Injury Relate to Confrontation Naming Performance.

Background: Traumatic brain injury (TBI) may confer risk for Alzheimer's disease (AD) through amyloid-ß (Aß) overproduction. However, the relationship between TBI and Aß levels in cerebrospinal fluid (CSF) remains unclear. Objective: To explore whether Aß overproduction is implicated in the relationship between TBI and AD, we compared CSF levels of Aß in individuals with a TBI history versus controls (CTRLs) and related CSF Aß levels to cognitive markers associated with preclinical AD. Methods: Participants were 112 non-impaired Veterans (TBI = 56, CTRL = 56) from the Alzheimer's Disease Neuroimaging Initiative-Department of Defense database with available cognitive data (Boston Naming Test [BNT], Rey Auditory Verbal Learning Test [AVLT]) and CSF measures of Aß42, Aß40, and Aß38. Mediation models explored relationships between TBI history and BNT scores with Aß peptides as mediators. Results: The TBI group had higher CSF Aß40 (t = -2.43, p = 0.017) and Aß38 (t = -2.10, p = 0.038) levels than the CTRL group, but groups did not differ in CSF Aß42 levels or Aß42/Aß40 ratios (p > 0.05). Both Aß peptides negatively correlated with BNT (Aß40: rho = -0.20, p = 0.032; Aß38: rho = -0.19, p = 0.048) but not AVLT (p > 0.05). Aß40 had a significant indirect effect on the relationship between TBI and BNT performance (ß= -0.16, 95% CI [-0.393, -0.004], PM = 0.54). Conclusions: TBI may increase AD risk and cognitive vulnerability through Aß overproduction. Biomarker models incorporating multiple Aß peptides may help identify AD risk among those with TBI.

Hybrid nucleobases as new and efficient unnatural genetic letters.

To expand the existing genetic letters beyond the natural four nucleotides, such as G, C, A, and T, it is necessary to design robust nucleotides that can not only produce stable and unperturbed DNA but also function naturally in living cells. Although hydrophobic bases, such as d5SICS (2,6-dimethyl-2H-isoquiniline-1-thione) and dNaM (2-methoxy-3-methylnaphthalene) were shown to be replicated in bacterial cells, the d5SICS:dNaM base-pair was found to perturb the structure of the duplex DNA. Therefore, it is necessary to design nucleobases that can form base pairs like the natural G:C and A:T pairs. Here, a reliable dispersion-corrected density functional theory has been used to design several nucleobases that can produce three-hydrogen-bonded base pairs like the G:C pair. In doing so, the Watson-Crick faces of d5SICS and dNaM were modified by replacing the hydrophobic groups with hydrogen bond donors and acceptors. As dNaM contains an unnatural C-glycosidic bond (C-dNaM), it was also modified to contain the natural N-glycosidic bond (N-dNaM). This technique produced 91 new bases (N-d5SICS-X (X = 1-33), C-dNaM-X (X = 1-35), and N-dNaM-X (X = 1-23), where X is the different types of modifications applied to d5SICS and dNaM) and 259 base-pairs. Among these base pairs, 76 base pairs are found to be more stable than the G:C pair. Interestingly, the N-d5SICS-32:C-dNaM-32 and N-d5SICS-32:N-dNaM-20 pairs are found to be the most stable with binding energies of about -28.0 kcal/mol. The base-pair patterns of these pairs are also analogous to that of the G:C pair. Hence, it is proposed that N-d5SICS-32, C-dNaM-32, and N-dNaM-20 would act as efficient new genetic letters to produce stable and unperturbed artificial DNA.Communicated by Ramaswamy H. Sarma.

Peptide inhibitors derived from the nsp7 and nsp8 cofactors of nsp12 targeting different substrate binding sites of nsp12 of the SARS-CoV-2.

SARS-COV-2 is responsible for the COVID-19 pandemic, which has infected more than 767 million people worldwide including about 7 million deaths till 5 June 2023. Despite the emergency use of certain vaccines, deaths due to COVID-19 have not yet stopped completed. Therefore, it is imperative to design and develop drugs that can be used to treat patients suffering from COVID-19. Here, two peptide inhibitors derived from nsp7 and nsp8 cofactors of nsp12 have been shown to block different substrate binding sites of nsp12 that are mainly responsible for the replication of the viral genome of SARS-CoV-2. By using the docking, molecular dynamics (MD), and MM/GBSA techniques, it is shown that these inhibitors can bind to multiple binding sites of nsp12, such as the interface of nsp7 and nsp12, interface of nsp8 and nsp12, RNA primer entry site, and nucleoside triphosphate (NTP) entry site. The relative binding free energies of the most stable protein-peptide complexes are found to lie between ∼-34.20 ± 10.07 to -59.54 ± 9.96 kcal/mol. Hence, it is likely that these inhibitors may bind to different sites of nsp12 to block the access of its cofactors and the viral genome, thereby affecting the replication. It is thus proposed that these peptide inhibitors may be further developed as potential drug candidates to suppress the viral loads in COVID-19 patients.Communicated by Ramaswamy H. Sarma.

Structure and stability of different triplets involving artificial nucleobases: clues for the formation of semisynthetic triple helical DNA.

A triple helical DNA can control gene expression, help in homologous recombination, induce mutations to facilitate DNA repair mechanisms, suppress oncogene formations, etc. However, the structure and function of semisynthetic triple helical DNA are not known. To understand this, various triplets formed between eight artificial nucleobases (P, Z, J, V, B, S, X, and K) and four natural DNA bases (G, C, A, and T) are studied herein by employing a reliable density functional theoretic (DFT) method. Initially, the triple helix-forming artificial nucleobases interacted with the duplex DNA containing GC and AT base pairs, and subsequently, triple helix-forming natural bases (G and C) interacted with artificial duplex DNA containing PZ, JV, BS, and XK base pairs. Among the different triplets formed in the first category, the C-JV triplet is found to be the most stable with a binding energy of about - 31 kcal/mol. Similarly, among the second category of triplets, the Z-GC and V-GC triplets are the most stable. Interestingly, Z-GC and V-GC are found to be isoenergetic with a binding energy of about - 30 kcal/mol. The C-JV, and Z-GC or V-GC triplets are about 12-14 kcal/mol more stable than the JV and GC base pairs respectively. Microsolvation of these triplets in 5 explicit water molecules further enhanced their stability by 16-21 kcal/mol. These results along with the consecutive stacking of the C-JV triplet (C-JV/C-JV) data indicate that the synthetic nucleobases can form stable semisynthetic triple helical DNA. However, consideration of a full-length DNA containing one or more semisynthetic bases or base pairs is necessary to understand the formation of semisynthetic DNA in living cells.

Repurposing of antiparasitic drugs against the NS2B-NS3 protease of the Zika virus.

To date, no approved drugs are available to treat the Zika virus (ZIKV) infection. Therefore, it is necessary to urgently identify potential drugs against the ZIKV infection. Here, the repurposing of 30 antiparasitic drugs against the NS2B-NS3 protease of the ZIKV has been carried out by using combined docking and molecular dynamics- (MD) simulations. Based on the docking results, 5 drugs, such as Amodiaquine, Primaquine, Paromomycin, Dichlorophene, and Ivermectin were screened for further analysis by MD simulations and free energy calculations. Among these drugs, Amodiaquine and Dichlorophen are found to produce the most stable complexes and possess relative binding free energies of about -44.3 ± 3.7 kcal/mol and -41.1 ± 5.3 kcal/mol respectively. Therefore, they would act as potent small-molecule inhibitors of the ZIKV protease.However, evaluations of biological and safety activities of these drugs against the ZIKV protease are required before their clinical use.Communicated by Ramaswamy H. Sarma.

Structures and dynamics of peptide and peptidomimetic inhibitors bound to the NS2B-NS3 protease of the ZIKA virus.

Infections caused by the Zika virus (ZIKV) have detrimental effects on human health, in particular on infants. As no potent drug or vaccine is available to date to contain this viral disease, it is necessary to design inhibitors that can target the NS2B-NS3 protease of the ZIKV, which is mainly responsible for the proliferation of the virus inside the host cells . Here, molecular dynamics (MD) simulation and molecular mechanics energies combined with the generalized Born and surface area continuum solvation model (MM/GBSA) are used to understand the binding modes and stabilities of R, KR, KKR, WKR, WKKR, YKKR, and FKKR peptide inhibitors bound to the NS3-NS2B protease. The results are compared with the corresponding results obtained for covalent (compound 1) and non-covalent (compound 4*) peptidomimetic inhibitors . It is revealed that peptide inhibitors can bind strongly with the ZIKV protease with the ΔGbind ranging from -12 kcal/mol to -73 kcal/mol. Among these peptides, YKKR is found to make the most stable complex with the protease and fully occupy the electrostatically active substrate binding site. Hence, it would inhibit the protease activities of ZIKV strongly. The residue-wise decomposition of ΔGbind indicates that Asp75, Asp129, Tyr130, Ser135, Gly151, Asn152, Glys153, and Tyr161 of NS3 and Ser81, Asp83, and Phe84 of NS2B play a prominent role in the inhibitor binding. Therefore, any future design of inhibitors should be aimed to target these residues.

Complementary base pair interactions between different rare tautomers of the second-generation artificial genetic alphabets.

The functionality of a semisynthetic DNA in the biological environment will depend on the base pair nature of its complementary base pairs. To understand this, base pair interactions between complementary bases of recently proposed eight second-generation artificial nucleobases are studied herein by considering their rare tautomeric conformations and a dispersion-corrected density functional theoretic method. It is found that the binding energies of two hydrogen-bonded complementary base pairs are more negative than those of the three hydrogen-bonded base pairs. However, as the former base pairs are endothermic, the semisynthetic duplex DNA would involve the latter base pairs.

Posttraumatic stress symptom severity predicts cognitive decline beyond the effect of Alzheimer's disease biomarkers in Veterans.

Chronic stress is a risk factor for dementia but whether it explains unique variance in cognitive decline in older adults above Alzheimer's disease (AD) biomarkers is unknown. In a preclinical cohort of Vietnam Veterans, we examined the relationship between posttraumatic stress disorder (PTSD) symptom severity, AD biomarkers of beta-amyloid (Aß) and tau, and change in cognitive performance on two widely-used screeners, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Analyses indicated that PTSD symptom severity was associated with a greater decline on the MMSE (p < 0.04) and MoCA (p < 0.024) after adjusting for biomarkers of AD, notably on the attention scale of the MoCA and the memory index of the MMSE. These analyses survived multiple comparison corrections. Taken together, PTSD symptom severity is associated with accelerated cognitive decline. Treating PTSD should be considered instrumental to maintaining cognitive function as adults age.

Artificially expanded genetic information systems (AEGISs) as potent inhibitors of the RNA-dependent RNA polymerase of the SARS-CoV-2.

The recent outbreak of the SARS-CoV-2 infection has affected the lives and economy of more than 200 countries. The unavailability of virus-specific drugs has created an opportunity to identify potential therapeutic agents that can control the rapid transmission of this pandemic. Here, the mechanisms of the inhibition of the RNA-dependent RNA polymerase (RdRp), responsible for the replication of the virus in host cells, are examined by different ligands, such as Remdesivir (RDV), Remdesivir monophosphate (RMP), and several artificially expanded genetic information systems (AEGISs) including their different sequences by employing molecular docking, MD simulations, and MM/GBSA techniques. It is found that the binding of RDV to RdRp may block the RNA binding site. However, RMP would acquire a partially flipped conformation and may allow the viral RNA to enter into the binding site. The internal dynamics of RNA and RdRp may help RMP to regain its original position, where it may inhibit the RNA-chain elongation reaction. Remarkably, AEGISs are found to obstruct the binding site of RNA. It is shown that dPdZ, a two-nucleotide sequence containing P and Z would bind to RdRp very strongly and may occupy the positions of two nucleotides in the RNA strand, thereby denying access of the substrate-binding site to the viral RNA. Thus, it is proposed that the AEGISs may act as novel therapeutic candidates against the SARS-CoV-2. However, in vivo evaluations of their potencies and toxicities are needed before using them against COVID-19.Communicated by Ramaswamy H. Sarma.

Contribution of cerebral microvascular mechanisms to age-related cognitive impairment and dementia.

Cognitive impairment and dementia are significant health burdens worldwide. Aging, hypertension, and diabetes are the primary risk factors for Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD). There are no effective treatments for AD/ADRD to date. An emerging body of evidence indicates that cerebral vascular dysfunction and hypoperfusion precedes the development of other AD pathological phenotypes and cognitive impairment. However, vascular contribution to dementia is not currently well understood. This commentary highlights the emerging concepts and mechanisms underlying the microvascular contribution to AD/ADRD, including hypotheses targeting the anterograde and retrograde cerebral vascular pathways, as well as the cerebral capillaries and the venous system. We also briefly discuss vascular endothelial dysfunction, oxidative stress, inflammation, and cellular senescence that may contribute to impaired cerebral blood flow autoregulation, neurovascular uncoupling, and dysfunction of cerebral capillaries and the venous system.

The COVID-19 Pandemic and Access to Selected Ambulatory Care Services Among Populations With Severely Uncontrolled Diabetes and Hypertension in Massachusetts.

OBJECTIVES: The outbreak of COVID-19 in Massachusetts may have reduced ambulatory care access. Our study aimed to quantify this impact among populations with severely uncontrolled diabetes and hypertension; these populations are at greatest risk for adverse outcomes caused by disruptions in care. METHODS: We analyzed multidisciplinary ambulatory electronic health record data from MDPHnet. We established 3 cohorts of patients with severely uncontrolled diabetes and 3 cohorts of patients with severely uncontrolled hypertension using 2017, 2018, and 2019 data, then followed each cohort through the subsequent 15 months. For the diabetes cohorts, we generated quarterly counts of glycated hemoglobin A1c (HbA1c) tests. For the hypertension cohorts, we generated monthly counts of blood pressure measurements. Finally, we assessed telehealth use among the 2019 diabetes and hypertension cohorts from January 2020 through March 2021. RESULTS: HbA1c testing and blood pressure monitoring dropped considerably during the pandemic compared with previous years. In the 2019 diabetes cohort, HbA1c measurements declined from 44.0% in January-March 2020 (baseline) to 15.9% in April-June 2020 and was 11.8 percentage points below baseline in January-March 2021. In the 2019 hypertension cohort, blood pressure measurements declined from 40.0% in January 2020 to 4.5% in April 2020 and was 23.5 percentage points below baseline in March 2021. Telehealth use increased precipitously during the pandemic but was not uniform across subpopulations. CONCLUSIONS: Access to selected diabetes and hypertension services declined sharply during the pandemic among populations with severely uncontrolled disease. Although telehealth is an important strategy, ensuring equity in access is essential. Telehealth hybrid models can also minimize disruptions in care.