Let's define $\delta(x) = (\sum_{{q\leq x}}{\frac{1}{q}}-\log \log x-B)$, where $B \approx 0.2614972128$ is the Meissel-Mertens constant. The Robin theorem states that $\delta(x)$ changes sign infinitely often. Let's also define $S(x) = \theta(x) - x$, where $\theta(x)$ is the Chebyshev function. It is known that $S(x)$ changes sign infinitely often. We define the another function $\varpi(x) = \left(\sum_{{q\leq x}}{\frac{1}{q}}-\log \log \theta(x)-B \right)$. We prove that when the inequality $\varpi(x) \leq 0$ is satisfied for some number $x \geq 3$, then the Riemann hypothesis should be false. The Riemann hypothesis is also false when the inequalities $\delta(x) \leq 0$ and $S(x)\geq 0$ are satisfied for some number $x \geq 3$ or when $\frac{3 \times \log x + 5}{8 \times \pi \times \sqrt{x} + 1.2 \times \log x + 2} + \frac{\log x}{\log \theta(x)} \leq 1$ is satisfied for some number $x \geq 13.1$.

Relationships between the Farey sequence and the Riemann hypothesis other than the Franel-Landau theorem are discussed. Whether a function similar to Chebyshev’s second function is square-root close to a line having a slope different from 1 is discussed. The nontrivial zeros of the Riemann zeta function can be used to approximate many functions in analytic number theory. For example, it could be said that the nontrival zeta function zeros and the Möbius function generate in essence the same function - the Mertens function. A different approach is to start with a sequence that is analogous to the nontrivial zeros of the zeta function and follow the same procedure with both this sequence and the nontrivial zeros of the zeta function to generate in essence the same function. A procedure for generating such a function is given.

Robin criterion states that the Riemann Hypothesis is true if and only if the inequality $\sigma(n) < e^{\gamma } \times n \times \log \log n$ holds for all natural numbers $n > 5040$, where $\sigma(n)$ is the sum-of-divisors function and $\gamma \approx 0.57721$ is the Euler-Mascheroni constant. Let $q_{1} = 2, q_{2} = 3, \ldots, q_{m}$ denote the first $m$ consecutive primes, then an integer of the form $\prod_{i=1}^{m} q_{i}^{a_{i}}$ with $a_{1} \geq a_{2} \geq \cdots \geq a_{m} \geq 0$ is called an Hardy-Ramanujan integer. If the Riemann Hypothesis is false, then there are infinitely many Hardy-Ramanujan integers $n > 5040$ such that Robin inequality does not hold and $n < (4.48311)^{m} \times N_{m}$, where $N_{m} = \prod_{i = 1}^{m} q_{i}$ is the primorial number of order $m$.

In this article, it is demonstrated that if the zeta function does not have a sequence of zeros whose real part converges to 1, then it cannot have any zeros in the critical strip, showing that the Riemann Hypothesis is false.

In this study, a simple approach to solving the Riemann Hypothesis, one of the most prominent unsolved problems in the field of Number Theory in mathematics and one of the “Millenium Prize Problems”, is presented. The Riemann Hypothesis, a conjecture about distribution of prime numbers, has remained unsolved since it was first proposed by German mathematician, Bernhard Riemann in 1859. This paper introduces an analytic continuation of the Zeta Function as well as symmetric approach through integration by parts to address this hypothesis. The proposed solution is obtained through analytical continuation in the critical strip 0<Re(s)<1 to establish that Re(s)=1/2.

Proof of the Riemann hypothesis is obtained using the properties of the Gamma function, the Bernoulli function, and limitations imposed by the rational relations of the complex roots of the Riemann zeta function, and the rational relations of the complex Gamma functions.

The basic idea is to expand the completed zeta function $\xi(s)$ in MacLaurin series (infinite polynomial), which can be further expressed as infinite product (Hadamard product) by conjugate complex roots. Finally, the functional equation $\xi(s)=\xi(1-s)$ leads to $(s-\alpha_i)^2 = (1-s-\alpha_i)^2, i \in \mathbb{N}$ with solution $\alpha_i= \frac{1}{2}, i \in \mathbb{N}$, where $\alpha_i$ are the real parts of the zeros of $\xi(s)$, i.e., $s_i =\alpha_i\pm j\beta_i, i\in \mathbb{N}$. Therefore, a proof of the Riemann Hypothesis is achieved.

In this paper we address some variants for the products of Hadamard and Patterson. We prove that all zeros of the Riemann $\Xi$--function are real. We also prove that the Riemann hypothesis is true. The equivalence theorems associated with the Riemann zeta--function are obtained in detail.

The Hamiltonian of a quantum mechanical system has an affiliated spectrum. If this spectrum is the sequence of prime numbers, a connection between quantum mechanics and the nontrivial zeros of the Riemann zeta function can be made. In this case, the Riemann zeta function is analogous to chaotic quantum systems, as the harmonic oscillator is for integrable quantum systems. Such quantum Riemann zeta function analogies have led to the Bender-Brody-Müller (BBM) conjecture, which involves a non-Hermitian Hamiltonian that maps to the zeros of the Riemann zeta function. If the BBM Hamiltonian can be shown to be Hermitian, then the Riemann Hypothesis follows. As such, herein we perform a symmetrization procedure of the BBM Hamiltonian to obtain a unique Hermitian Hamiltonian that maps to the zeros of the analytic continuation of the Riemann zeta function, and provide an analytical expression for the eigenvalues of the results. The holomorphicity of the resulting eigenvalues is examined. Moreover, a second quantization of the resulting Schrödinger equation is performed, and a convergent solution for the nontrivial zeros of the analytic continuation of the Riemann zeta function is obtained. Finally, from the holomorphicity of the eigenvalues it is shown that the real part of every nontrivial zero of the Riemann zeta function converges at σ = 1/2.

In this paper, we derive Von Koch's inequality without using the Riemann Hypothesis. As well known, Von Koch's inequality is equivalent to the Riemann Hypothesis. Namely, we show that the Riemann Hypothesis is true. Furthermore, we show that the upper limit of its can be lowered.

A concise proof of the Riemann Hypothesis is presented by clarifying the Hadamard product expansion over the zeta zeros, demonstrating that the Riemann Hypothesis is true.

This work uses a new approach to investigate the Riemann hypothesis, drawing conclusions about its trueness. It is based on the more general method presented in a very recent publication, by the same author, showing in detail how to approach that very well-known and interesting problem. This is achieved by means of the theory of dynamical systems (Poincaré index associated to equilibria of 2-dimensional systems) and the study of the zeros of the Dirichlet eta function, defined by a Dirichlet series. By using the well-known fact that the zeros of the eta function include all zeros of the Riemann zeta function in the (open) critical strip, excluded the critical line, ((0,1/2) ∪ (1/2,1)) × (−∞,∞), the development proceeds using only the eta function. In addition, the open and simply connected region (1/2,1) × (0,∞) is used along the text, taking into account the symmetries of zeros of the functions under analysis in the critical strip. The basic line of proof is to find the mathematical expression for the Poincaré index of the vector field associated to the eta function, assuming the existence of a zero of the eta function outside the critical line (in (1/2,1) × (0,∞)), and investigating the resulting unfoldings. Eventually, an inconsistency occurs and the proof ends by contradiction.

A probabilistic description is essential for understanding the dynamics of stochastic systems far from equilibrium, given uncertainty inherent in the systems. To compare different Probability Density Functions (PDFs), it is extremely useful to quantify the difference among different PDFs by assigning an appropriate metric to probability such that the distance increases with the difference between the two PDFs. This metric structure then provides a key link between stochastic systems and information geometry. For a non-equilibrium process, we define an infinitesimal distance at any time by comparing two PDFs at times infinitesimally apart and sum these distances in time. The total distance along the trajectory of the system quantifies the total number of different states that the system undergoes in time, and is called the information length. By using this concept, we investigate the information geometry of non-equilibrium processes involved in disorder-order transitions between the critical and subcritical states in a bistable system. Specifically, we compute time-dependent PDFs, information length, the rate of change in information length, entropy change and Fisher information in disorder-to-order and order-to-disorder transitions, and discuss similarities and disparities between the two transitions. In particular, we show that the total information length in order-to-disorder transition is much larger than that in disorder-to-order transition, and elucidate the link to the drastically different evolution of entropy in both transitions. We also provide the comparison of the results with those in the case of the transition between the subcritical and supercritical states and discuss implications for fitness.

In this article, we present solutions for one of the oldest mathematical problems, the Collatz Conjecture, and provide a proof for the Riemann Hypothesis, utilizing a new number theory based on newly discovered number properties, which will also be presented in this paper. This is made possible through the Sophy-Peter mathematical framework, built upon this new number theory. The Collatz Conjecture will be disproven, but as an alternative, the Oscillating Theorem will be introduced, with its correctness proven within this article. Furthermore, we present the general version of the Riemann zeta function, developed based on the new number theory. The correctness of this function is verified by comparing it with existing results of the zeta function. Using this approach and the Sophy-Peter framework, we have successfully proven the Riemann Hypothesis, long considered a millennium problem. Moreover, since the general zeta function is proven, this implies the correctness of the new number theory and the Sophy-Peter framework.

Prime numbers are the atoms of mathematics and mathematics is needed to make sense of the real world. Finding the Prime number structure and eventually being able to crack their code is the ultimate goal in what is called Number Theory. From the evolution of species to cryptography, Nature finds help in Prime numbers. One of the most important advances in the study of Prime numbers was the paper by Bernhard Riemann in November 1859 called “Ueber die Anzahl der Primzahlen unter einer gegebenen Grösse” (On the number of primes less than a given quantity). In that paper, Riemann gave a formula for the number of primes less than x in terms the integral of 1/log(x) and the roots (zeros) of the zeta function defined by: Where ζ(z) is a function of a complex variable z that analytically continues the Dirichlet series. Riemann also formulated a conjecture about the location of the zeros of RZF, which fall into two classes: the "trivial zeros" -2, -4, -6, etc., and those whose real part lies between 0 and 1. Riemann's conjecture Riemann hypothesis [RH] was formulated as this: [RH] The real part of every nontrivial zero z* of the RZF is 1/2. Proving the RH is, as of today, one of the most important problems in mathematics. In this paper we will provide a proof of the RH. The proof of the RH will be built following these five parts: PART 1: Description of the RZF PART 2: The C-transformation PART 3: Application of the C-transformation to in Re(z) 0 to obtain ζ(z)=X(z)-Y(z) PART 4: Analysis of the values of z such that X(z)=Y(z), and |X(z)|=|Y(z)|, that equates to ζ(z)=0 Proof that |X(z)|=|Y(z)| only if Re(z)=1/2 Conclude that ζ(z)=0 only if Re(z)=1/2 for Re(z) 0 PART 5: We will also prove that all non-trivial zeros of ζ(z) in the critical line of the form are not distributed randomly. There is a relationship between the values of those zeros and the Harmonic function that leads to an algebraic relationship between any two zeros.

One of the most important unresolved mysteries in mathematics is the Riemann Hypothesis, which suggests a fundamental connection between the non-trivial zeros of the Riemann zeta function and the distribution of prime numbers. Here, we explore the fascinating union of trigonometric functions, prime numbers, and the Riemann zeta function through an examination of the zeros in the statement ln(sec(π·n log(n))). We demonstrate a strong mathematical connection between these components, providing information on the mysterious properties of prime numbers and their complex relationships to basic mathematical operations. Our thorough investigation adds to the current discussion of the Riemann Hypothesis by offering possible solutions and deepening our comprehension of the intricate relationship between number theory and analytic functions.

The Mara River basin (MRB) has a world-famous ecosystem, but the vegetation has been damaged due to economic development in recent years, and there is little known about the area that will experience severe vegetation damage in the future. Based on the vegetation vulnerability system, principal component analysis, and three CMIP6 scenarios (SSP1-2.6, SSP2-4.5, SSP5-8.5), vegetation vulnerability was calculated in the base period (2010-2019), near-term period (2020-2059) and long-term period (2060-2099) in the MRB. The spatial cluster of vegetation vulnerability was revealed by spatial correlation analysis, and the transition of vegetation vulnerability of different periods was analyzed by stochastic matrix. The results showed that in all periods, the vulnerability showed a high-high cluster in the east, and a low-low cluster midstream and downstream. From the stochastic matrix, the area of high vulnerability increased the least under the SSP1-2.6, while it increased the most under the SSP5-8.5. The vegetation vulnerability upstream increased the most from the base period to the near-term period and long-term period in the MRB. By comparing the vegetation vulnerability under different scenarios, and pointing out the areas with the highest vulnerability increase, this study can better provide comprehensive decision-making for vegetation protection in the MRB.

Introduction: Leprosy, caused by Mycobacterium leprae is one of the oldest infectious diseases in human history and its eradication is linked to poverty control, lack of basic sanitation, the fragility of health, and education services. Objective: To evaluate the frequency of blood groups (ABO/Rh) and the sociodemographic and clinical profile of Angolan patients with Leprosy treated at the Anti-Tuberculosis and Leprosy Dispensary in Luanda, the capital city of Angola. Methodology: A descriptive, introspective, cross-sectional study with a quantitative approach was carried out with 102 patients of Luanda, in the second half of 2021. Results: Of the 102 patients included in the study, the majority belonged to the ORh+ group (51.9%), followed by the BRh+ group (27.4%) and ARh+ (18.6%), most were under 51 years of age ( 87.3%), with low education (54.9%), coming from urban areas (44.1%). As for clinical conditions, most had a multibacillary infection (93.1%), diagnosed mainly by smear microscopy (75.5%) without other infection (79.4%), some of them with complications (28.4%) and individuals with non-O blood group showed changes in the blood count. Conclusion: Leprosy seems to be common in ORh+ individuals, it continues to affect especially those residing in areas of population agglomerations and with low education, presenting itself as a multibacillary infection, where changes in the blood count are greater in non-O individuals.

The philosophy of testing statistical hypothesis is a natural consequence and functional extension of mathematical analysis of Probability. Along with the concept of recurrence when applied to random sequences and functions, it leads to the analysis of a priori and posterior which implies testing statistical hypothesis. Testing statistical hypothesis also involves algebraic, functional and dimensional considerations, which are found in the works of Laplace. Aspects of mathematical analysis such as universality of solutions, Laws of Large Numbers, Entropy, Information, and various functional dependencies are the main factors explained in the five properties that lead to implication of testing statistical hypothesis. Various interesting examples with modern scientific significance from genetics, astrophysics, and other areas give methodological access to answers of different problems and phenomena which are involved in the logic of testing statistical hypothesis.

The recent measurement of a cutoff k_min in the fluctuation power spectrum P(k) of the cosmic microwave background may vitiate the possibility that slow-roll inflation can simultaneously solve the horizon problem and account for the formation of structure via the growth of quantum fluctuations in the inflaton field. Instead, we show that k_min may be interpreted more successfully in the R_h=ct cosmology, as the first mode exiting from the Planck scale into the semi-classical Universe shortly after the Big Bang. In so doing, we demonstrate that such a scenario completely avoids the well-known trans-Planckian problem plaguing standard inflationary cosmology, with some additional clues that may motivate further development of Kaluza-Klein cosmologies, string theories and supergravity.

In this research a neccessary and sufficient condition for the proof of the Binary Goldbach conjecture is established. It is established that the square of all natural numbers greater or equal to 2 have an additive partition equal to the sum of the square of a natural number greater or equal to zero and a Goldbach partition semiprime. All Goldbach partition semiprimes are odd except 4. This finding is in itself proof all composite even numbers have at least Goldbach partition. The result of the proof of the Binary Goldbach conjecture is used to prove the Andrica and Legendre conjectures. The Riemann hypothesis is examined and sources of non trivial zeroes outside the critical strip are discussed. An example example of a non-trivial zero outside the critical strip is given

This paper attempts to propose a Riemann spring model via an analogy between the Riemann Zeta function of a complex number and the elastic spring in series.

Electrochemical Promotion was used to modify the activity and selectivity of a Rh catalyst-electrode in the CO2 hydrogenation reaction. The experiments were carried out in a temperature range of 350-430οC at ambient pressure and at different CO2 to H2 gas feeding ratios (1:2 to 4:1). The only reaction products observed were CO and CH4, both under open and closed-circuit conditions. The CH4 formation rate was found to increase with both positive and negative potential or current application. The CO formation rate followed the opposite trend. The selectivity to CH4 increased under high values of hydrogen partial pressure and decreased at high pressures of CO2. The results demonstrate how Electrochemical Promotion can be used to finely tune activity and selectivity for a reaction of high technical and environmental importance.

Riemann’s method is one of the definitive ways of solving Cauchy’s problem for a second order linear hyperbolic partial differential equation in two variables. The first review of Riemann’s method was published by E. T. Copson in 1958. This study extends that work. Firstly, three solution methods were overlooked in Copson’s original paper. Secondly, several new approaches for finding Riemann functions have been developed since 1958. Those techniques are included here and placed in the context of Copson’s original study. There are also numerous equivalences between Riemann functions that have not previously been identified in the literature. Those links are clarified here by showing that many known Riemann functions are often equivalent due to the governing equation admitting a symmetry algebra isomorphic to $SL(2,R)$. Alternatively, the equation admits a Lie-Bäcklund symmetry algebra. Combining the results from several methods, a new class of Riemann functions is then derived which admits no symmetries whatsoever.

Background: In most cases, intra-labyrinthine schwannoma (ILS) occurs in patients with unilateral hearing deterioration or neurofibromatosis type II (NF II). The pattern of localization of these tumors is various but affects mostly the cochlea. Extirpation of the ILS, if hidden by the cochlea modiolus, is difficult under the aspect of complete removal. Therefore, a tissue removal device (TRD) was designed and tested in temporal bones. The principle of handling the new device is a pushing and pipe cleaner handling inside the cochlea. This present study aimed to describe the first in vivo experience with the newly developed TRD for removing cochlear intra-labyrinthine schwannoma. Methods: In three patients, the TRD was used for the tumor removal of ILS. In two patients with a cochlear schwannoma in combination with a cochlea implantation and one patient suffering from NF II, a cochlear schwannoma was removed with the TRD. The access was performed with a posterior tympanotomy, an enlarged round window approach, and an additional second-turn access. The device was inserted and extracted gradually from the second turn access until the rings were visible in the second turn access. By pushing and pipe cleaner handling, the tumors were removed. An MRI control was performed on the day postoperatively with a T1 GAD sequence. Results: Tumor removal with the TRD was performed in a 15-minute procedure. MRI control confirmed a complete removal on the postoperative day in both cases. Conclusion: In vivo handling of the device confirmed a straightforward handling for tumor removal. MRI scanning showed a complete removal of the tumor by the TRD.

Maternal obesity and gestational diabetes mellitus (GDM) are linked with impaired placental function and early onset of non-communicable cardiometabolic diseases in offspring. Previous studies have highlighted that the dietary non-esterified fatty acids (NEFAs), palmitate (PA) and oleate (OA), key dietary metabolites associated with maternal obesity and GDM, are potential modulators of placental lipid processing. Using the BeWo cell line model, the current study integrated transcriptomic (mRNA microarray), metabolomic, and lipidomic readouts to characterize the underlying impacts of exogenous PA and OA on placental villous trophoblast cell metabolism. Targeted gas chromatography and thin layer chromatography highlighted that saturated and monounsaturated NEFAs differentially impact BeWo cell lipid profiles. Furthermore, cellular lipid profiles differed when exposed to single and multiple NEFA species. Additional multi-omic analyses suggested that PA exposure is associated with enrichment in β-oxidation pathways, while OA exposure is associated with enrichment in anti-inflammatory and antioxidant pathways. Overall, this study further demonstrated that dietary PA and OA are important regulators of placental lipid metabolism. Encouraging appropriate dietary advise and implementing dietary interventions that maintain appropriate placental function by limiting excessive exposure to saturated NEFAs such as PA, will continue to be crucial in the clinical management of at-risk obese and GDM pregnancies.

Theoretical physics addresses the fundamental principles of nature and the mysteries of the universe. In the last century, the theory of relativity challenged people's understanding of time and space, while quantum mechanics revealed various forms of energy. However, the concept of gravity remains elusive. All matter in the universe is composed of energy that can be converted into other forms, yet it is always conserved. However, achieving a state of equilibrium, represented by the equal sign, can be challenging to achieve on both macro and quantum scales. A phenomenon that can transition from one state to infinity is called collision and is essential for understanding natural phenomena and physical processes throughout the universe. In the study of general relativity cannot be three-dimensional problems to gain mathematical inspiration, understand the application of new dimensions. Here, we elucidate the nature of gravity, which inspires the solution of the Riemann hypothesis. Our results show that the conduction mode of dimensional energy is defined by Euler's formula.

Arctic feedbacks will accelerate climate change and could jeopardise mitigation efforts. The permafrost carbon feedback releases carbon to the atmosphere from thawing permafrost and the sea ice albedo feedback increases solar absorption in the Arctic Ocean. A constant positive albedo feedback and zero permafrost feedback have been used in nearly all climate policy studies to date, while observations and models show that the permafrost feedback is significant and that both feedbacks are nonlinear. Using novel dynamic emulators in the integrated assessment model PAGE-ICE, we investigate nonlinear interactions of the two feedbacks with the climate and economy under a range of climate scenarios consistent with the Paris Agreement. The permafrost feedback interacts with the land and ocean carbon uptake processes, and the albedo feedback evolves through a sequence of nonlinear transitions associated with the loss of Arctic sea ice in different months of the year. The US’s withdrawal from the current national pledges could increase the total discounted economic impact of the two Arctic feedbacks until 2300 by $25 trillion, reaching nearly $120 trillion, while meeting the 1.5 °C and 2 °C targets will reduce the impact by an order of magnitude.

Although the dopamine hypothesis of schizophrenia explains the effects of all the available antipsychotics in clinical use, there is an increasing need for developing new drugs for the treatment of positive, negative, and cognitive symptoms of chronic psychoses. Xanomeline-trospium (KarXT) is a drug combination that is based on the essential role played by acetylcholine in the regulation of cognitive processes and the interactions between this neurotransmitter and other signaling pathways in the central nervous system, with a potential role in the onset of schizophrenia, Alzheimer’s disease, and substance use disorders. A systematic literature review that included four electronic databases (PubMed, Cochrane, Clarivate/Web of Science, and Google Scholar) and the US National Library of Medicine database for clinical trials detected 21 sources referring to 14 studies focused on KarXT, out of which only four have published results. Based on the results of these trials, the short-term efficacy and tolerability of xanomeline-trospium are good, but more data is needed before this drug combination may be recommended for clinical use. However, on a theoretical level, the exploration of KarXT is useful for increasing the interest of researchers in finding new, non-dopaminergic, antipsychotics that could be used either as monotherapy or as add-on drugs.

We review a theory that predicts the onset of thermalization in a quantum mechanical coupled non-linear oscillator system, which models the vibrational degrees of freedom of a molecule. A system of N non-linear oscillators perturbed by cubic anharmonic interactions exhibits a many-body localization (MBL) transition in the vibrational state space (VSS) of the molecule. This transition can occur at rather high energy in a sizable molecule because the density of states coupled by cubic anharmonic terms scales as ~ N3, in marked contrast to the total density of states, which scales as exp(aN), where a is a constant. The emergence of a MBL transition in the VSS is seen by analysis of a random matrix ensemble that captures the locality of coupling in the VSS, referred to as local random matrix theory (LRMT). Upon introducing higher order anharmonicity, the location of the MBL transition of even a sizable molecule, such as an organic molecule with tens of atoms, still lies at an energy that may exceed the energy to surmount a barrier to reaction, such as a barrier to conformational change. Illustrative calculations are provided, and some recent work on the influence of thermalization on thermal conduction in molecular junctions is also discussed.

In this article the reduction of a $n$-dimensional space to a $k$-dimensional space is considered as a reduction of $N^n$ states to $N^k$ states, where $N$ stands for the number of single-particle states per unit of spatial length. It turns out, this space reduction could be understood as another definition of inflation. It is shown that the introduction of the non-associativity of the algebra of physical fields in a homogeneous space leads to a nonlinear equation, the solutions of which can be considered as two-stage inflation. Using the example of reduction $T\times R^7$ to $T\times R^3$, it is shown that there is a continuous cross-linking of the Friedmann and inflationary stages of algebraic inflation at times $10^{-15}$ with the number of baryons $10^{80}$ in the Universe. In this paper, we construct a new gravitational constant based on a nonassociative octonion algebra.

In this article the reduction of a $n$-dimensional space to a $k$-dimensional space is considered as a reduction of $N^n$ states to $N^k$ states, where $N$ stands for the number of single-particle states per unit of spatial length. It turns out, this space reduction could be understood as another definition of inflation. It is shown that the introduction of the non-associativity of the algebra of physical fields in a homogeneous space leads to a nonlinear equation, the solutions of which can be considered as two-stage inflation. Using the example of reduction $T\times R^7$ to $T\times R^3$, it is shown that there is a continuous cross-linking of the Friedmann and inflationary stages of algebraic inflation at times $10^{-15}$ with the number of baryons $10^{80}$ in the Universe. In this paper, we construct a new gravitational constant based on a nonassociative octonion algebra.

Bone morphogenetic proteins (BMPs), belonging to the transforming growth factor-β superfamily, regulate many cellular activities including proliferation and neovascularization. The use of recombinant human bone morphogenic protein 2 (rh-BMP 2) in oral and maxillofacial surgery has seen a tremendous increase, especially with bone grafting materials to promote bone reconstruction processes; even though its interactions with the other essential processes in the human tissues are still not fully clear. investigating the effect of administrating rh-bmp2 on the clinical values of the gingival cell proliferation index Ki67 marker expression in the gingival tissue in comparison with normal human gingival tissue. The study includes 2 groups in a randomized controlled Clinical Trial: 40 gingival samples; 20 normal and 20 have been treated with 0.25µg of rh-BMP2 during dental implantation in the posterior mandible area, taken 3 months later in the time of healing abutments installation using a tissue puncher. Samples will be stained with hematoxylin-eosin and immunohistochemically. The expression of Ki67 will be measured in one way: the number of cells that express the marker. The comparison between groups will be done using One -a way ANOVA test in the numerical data SPSS 17.0 will be used as software. Differences would be considered significant at P=0.05. It is considered that rh-BMP2 can improve gingival tissue proliferation in patients undergoing dental implant treatment, and indicates better healing.

In T. gondii, as well as in other model organisms, gene knock-out using CRISPR-Cas9 is a suitable tool to identify the role of specific genes. The general consensus implies that only the gene of interest is affected by the knock-out. Is this really the case? In a previous study, we have generated knock-out (KO) clones of TgRH88_077450 (SRS29B; SAG1) which differed in the numbers of integrated dihydrofolate-reductase-thymidylate-synthase (MDHFR-TS) drug-selectable marker. Clones 18 and 33 had a single insertion of MDHFR-TS within SRS29B. Clone 6 was disrupted by the insertion of a short unrelated DNA-sequence, but the marker was integrated elsewhere. In clone 30, the marker was inserted into SRS29B and several other MDHFR-TS copies were found in the genome. KO and wild-type (WT) tachyzoites had similar shape, dimensions and vitality. This prompted us to investigate the impact of the genetic engineering as such on the overall proteome patterns of the four clones as compared to the respective WT. Comparative shotgun proteomics of the five strains was performed. Overall, 3236 proteins were identified. Principal component analysis of the proteomes revealed five distinct clusters corresponding to the five strains by both iTop3 and iLFQ algorithms. Detailed analysis of the differentially expressed proteins revealed that the target of the KO, srs29B, was lacking in all KO clones. Besides this protein, twenty other proteins were differentially expressed between KO clones and WT or between different KO clones. The protein exhibiting the highest variation between the five strains was srs36D encoded by TgRH_016110. The deregulated expression of SRS36D was further validated by quantitative PCR. Moreover, the transcript levels of three other selected SRS genes, namely SRS36B, SRS46, and SRS57 exhibited significant differences between individual strains. These results indicate that knocking out a given gene may affect the expression of other genes. Therefore, care must be taken when specific phenotypes are regarded as a direct consequence of the KO of a given gene.

This paper attempts to extend the Riemann Zeta function of a complex number to a function of a matrix and/or a tensor $A$, namely $$\zeta (A)=\sum _{n=1}^{\infty} \frac{1}{n^{A}}= \sum _{n=1}^{\infty} \sum_{k=1}^n\lambda_k A^k$$ and inverse $$A=\sum _{n=1}^{\infty} \sum_{k=1}^n \mu(n)\lambda_k \zeta(A^k)$$ where $\mu(n)$ is the M\"obius function, $A$ is a complex matrix or tensor with any order, and $\lambda_k$ is eigenvalue of the matri/tensor $A$. This kind of calculations on the Riemann Zeta function has never been seen in the literature. Some examples are provided.

This paper shows that by applying the Nyquist-Shannon sampling theorem, the spatial and temporal resolution of a simulation can be no more than half the resolution of the simulating reality. This has significant implications for not only the values of the observables in the simulation but also its physical laws. This progressive halving of nested simulations coupled with the minimum resolution compatible with the production of a simulation also sets a limit to the nestedness of a lineage of simulations (it is by no means infinite). The limit of nestedness is then used to calculate the probability that we are living in a simulation assuming a single base reality. This will be shown to be significantly lower than popular expectation. A Kardashev-like scale, with three variants, is also developed to gauge the technological advancement of a civilization in relation to the extent to which it can extract information from space and time.

Recent lines of evidence suggest the intriguing hypothesis that consuming common culinary herbs of the mint family might help prevent or treat Covid. Individual citizens could easily explore the hypothesis using ordinary kitchen materials. I offer a philosophical framework to account for the puzzling lack of public health messaging about this interesting idea.

I propose a dynamic evolution hypothesis regarding the evolution of organisms by incorporating both diminished fitness returns and mutation rate tuning during adaptation to a constant environment. Basically, accumulating evidence from life history studies conducted over the past 70 years suggests that the evolution of individual fitness is subject to ecological constraints, leading to the evolutionary existence of an upper limit of individual fitness (ULIF). Given the existence of the ULIF, organismal evolution, which might initially have relatively great fitness returns through primarily Darwinian evolution, will eventually be subject to diminished fitness returns towards zero. With the diminished fitness return, Darwinian selection strength may eventually become smaller than the power of random genetic drift, leading to the occurrence of neutral evolution at both phenotypic and molecular levels. Meanwhile, mutation rates may change from an initial increase, due to the relatively strong fitness return, to subsequent decreases, due to both the diminished fitness return of beneficial mutations and the cost of deleterious mutations. The diminished fitness returns with subsequently reduced mutation rates are two potential evolution barriers leading to eventual evolutionary stasis. These findings provide important insights for understanding the conditions for the occurrences of different evolutionary patterns. Darwinian evolution theory, neutral evolution theory and punctuated equilibrium theory can be unified in the context of the dynamic evolution hypothesis formulated in this study.

The standard approach to integrable nonlinear evolution equations (NLEE) usually uses the following steps: 1) Lax representation $[L,M]=0$; 2)~construction of fundamental analytic solutions (FAS); 3) reducing the inverse scattering problem (ISP) to a Riemann-Hilbert problem (RHP) $\xi^+(x,t,\lambda) =\xi^-(x,t,\lambda) G(x,t\lambda)$ on a contour $\Gamma$ with sewing function $G(x,t,\lambda)$; 4) soliton solutions and possible applications.Step 1) involves several assumptions: the choice of the Lie algebra $\mathfrak{g}$ underlying $L$, as well as its dependence on the spectral parameter, typically linear or quadratic in $\lambda$. In the present paper we propose another approach which substantially extends the classes of integrable NLEE.Its first advantage is that one can effectively use any polynomial dependence in both $L$ and $M$. We use the following steps: A) Start with canonically normalized RHP with predefined contour $\Gamma$; B) Specify the $x$ and $t$ dependence of the sewing function defined on $\Gamma$; C) Introduce convenient parametrization for the solutions $ \xi^\pm(x,t,\lambda)$ of the RHP and formulate the Lax pair and the nonlinear evolution equations (NLEE); D) use Zakharov-Shabat dressing method to derive their soliton solutions. This needs correctly taking into account the symmetries of the RHP. E) Define the resolvent of the Lax operator and use it analyze its spectral properties.

Starting with unitary quantum dynamics, we investigate how to add quantum measurements. Quantum measurements have four essential components: the furcation, the witness production, an alignment projection, and the actual choice decision. The first two components still lie in the domain of unitary quantum dynamics. The decoherence concept explains the third contribution. It can be based on the requirement that witnesses reaching the end of time on the wave function side and the conjugate one have to be identical. In this way, it also stays within the quantum dynamics domain. The surjection hypothesis explains the actual choice decision. It is based on a two boundary interpretation applied to the complete quantum universe. It offers a simple way to reduce these seemingly random projections to purely deterministic unitary quantum dynamics, eliminating the measurement problem.

In this paper we provide amongst others some simple error bounds in approximating the weighted Riemann-Stieltjes integral $\int_{a}^{b}f\left(t\right) g\left(t\right) dv\left(t\right) $ by the use of three points formula \begin{equation*} f\left(b\right) \int_{c}^{b}g\left(s\right) dv\left(s\right) +f\left(a\right) \int_{a}^{d}g\left( s\right) dv\left( s\right) -f\left(x\right) \int_{c}^{d}g\left(t\right) dv\left(t\right) \end{equation*} where $x,$ $c,$ $d\in \left[a,b\right],$ $g,$ $v:\left[a,b\right] \rightarrow \mathbb{C}$ under bounded variation and Lipschitzian assumptions for the function $f$ and such that the involved Riemann-Stieltjes integrals exist.

Endometriosis is an oestrogen-dependant reproductive disease, with genetic, vascular, neural, inflammatory and auto-immune characteristics. There are many theories about the etiology of endometriosis, however, all of these theories have limitations and do not explain all the locations that endometriosis is found or types of patients with endometriosis. The objective of this paper is to postulate the hypothesis that endometriosis is caused by Maternal Microchimerism, the presence of maternal cells in the fetus. A literature review was conducted, analysing the characteristics, current etiological theories of endometriosis, theory limitations and relationship of maternal microchimerism and endometriosis. At time of writing, there was no literature on maternal microchimerism and endometriosis. These results suggest that Maternal Microchimerism could be a cause of endometriosis. This could account for the genetic and auto-immune characteristics seen in people with endometriosis, inducing a micro-environment for vascular, neural and epigenetic changes. This could also account for account for endometriosis seen in non-menstruating patients, such as men, fetuses and post-menopausal women and endometriosis found in non-peritoneal locations. If the hypothesis of Maternal Microchimerism is correct, endometriosis could be considered a pregnancy-related disease that could affect all humans, changing the accepted demographics of patients and potentially new diagnostic techniques and treatment options for patients with endometriosis. Further studies are needed to test this hypothesis.

Leigh Van Valen was an American evolutionary biologist who made major contributions to evolutionary theory and is particularly remembered by his groundbreaking paper "A New Evolutionary Law" (1973) where he provided evidence from fossil record data that this law maintains that the probability of extinction within any group remains es­sentially constant through time. In order to explain such unexpected result, Van Valen formulated a very influential idea that he dubbed the "Red Queen hypothesis". It states that the constant decay must be a consequence of evolutionary interactions among connected species within ecological networks. In Van Valen's picture, species do not merely evolve: they also coevolve with other species. As a consequence, when thinking in adaptation to an external environment, the other species must be considered as part (may be a major part) of such external world. Van Valen's law provided the first complex systems theory of coevolutionary dynamics and inspired a whole range of theoretical and experimental developments and scholars from very diverse fields, from economics to physics. In that respect, Leigh Van Valen's contribution percolated far beyond its original formulation. Red Queen arms races are nowadays considered a widespread feature of complex adaptive systems.

Particles are considered temporarily identical if the interchange of these particles does not cause any observable physical effects within a time interval Δt. An indistinguishability hypothesis is proposed for such particles, suggesting that two particles (or systems) with nearly the same degree of internal freedom will actually interchange under certain circumstances, thereby affecting the subsequent dynamics. This indistinguishability implies that, theoretically, it is possible to capture an elementary particle with extraordinarily large internal freedom by trading it for an isolated composite system of ordinary matter particles with almost the same total internal freedom as the large-freedom particle. Following this, the ordinary particles will instantly disperse into the environment, while the large-freedom particle will initially be captured and then gradually delocalized into the environment, an observable phenomenon. If this hypothesis is proven true in the future, it might provide a novel strategy for detecting dark matter particles.

In this article we propose the integral, series and product representations for the Ramanujan zeta-function. We suggest a variant for the Conrey-Ghosh product for the entire Ramanujan zeta-function. We present some variants for the product for the Ramanujan $\Xi$-function. We prove that all of its zeros are real. Along the way we obtain the truth of the Riemann-Hardy conjecture.

In this paper we establish some generalizations of Opial’s inequal- ities for Riemann-Stieltjes integral and for two functions. Applications related to trapezoid and Grüss’ ’type inequalities are also given.

The main objective of this present paper is to establish the extension of an extended fractional derivative operator by using an extended beta function recently defined by Parmar et al. by considering the Bessel functions in its kernel. Also, we give some results related to the newly defined fractional operator such as Mellin transform and relations to extended hypergeometric and Appell's function via generating functions.

A wide range of research has been developed in the empirical literature regarding income and price elasticities of health care expenditure (HCE). The results are mixed, as researchers employ different methodologies and data sources. The benefits of the panel data method, such as greater data variation, less collinearity, and more degrees of freedom, made it attractive among economists. However, the pooled mean group (PMG) method provides robust estimates compared to conventional methods, such as the mean group estimator and dynamic fixed-effects estimator. As such, this paper applies the PMG method to scrutinize the effect of income and price on U.S. health care consumption using a panel of 46 states. The income and price elasticities were found to be 0.85 and -0.48, respectively, which partially describes the recessionary decline in health care consumption following the Great Recession. In addition, the model reveals that the short-run income elasticity is smaller than the long-run. This confirms that U.S. health care consumption follows the permanent income hypothesis. Consequently, the short-run efficacy of public policies targeting HCE remains limited. The results of this paper suggest reconsidering and adjusting health care policies during a recession so as to avoid probable long-run adverse effects on HCE.

This research paper aims to explicate the complex issue of the Riemann's Hypothesis and ultimately presents its elementary proof. The method implements one of the binomial coefficients, to demonstrate the maximal prime gaps bound. Maximal prime gaps bound constitutes a comprehensive improvement over the Bertrand's result, and becomes one of the key elements of the theory. Subsequently, implementing the theory of the primorial function and its error bounds, an improved version of the Gauss' offset logarithmic integral is developed. This integral serves as a Supremum bound of the prime counting function Pi(n). Due to its very high precision, it permits to verify the relationship between the prime counting function Pi(n) and the offset logarithmic integral of Carl Gauss. The collective mathematical theory, via the Niels F. Helge von Koch equation, enables to prove the RIemann's Hypothesis conclusively.

Introduction: This study aimed to validate the psychometric properties of the German eHealth Impact Questionnaire (eHIQ-G), which is divided into two independently administered and scored parts. Methods: 162 people with MS browsed one of two possible websites containing information on MS and completed an online survey. Internal consistency was assessed by Cronbach’s alpha and structural validity by Confirmatory Factor Analysis. Construct validity was examined by assessing correlations with the eHealth Literacy Questionnaire and the General Self-Efficacy Scale. Moreover, the mean difference of the eHIQ-G score between the two websites was investigated. Results: Cronbach’s alpha for the eHIQ-G subscales ranged from .833 to .885. The eHIQ-G part 1 achieved acceptable levels of goodness-of-fit indices, whereas the fit for the eHIQ-G part 2 was poor and likewise for the alternative modified models. The correlations with the reference instruments were 0.08 – 0.62 and as expected. Older age was related with lower eHIQ-G part 1 score, whereas no significant effect was found for education. Although not significant, the website ‘AMSEL’ reached higher mean scores on eHIQ part 2. Conclusion: The eHIQ-G has good internal consistency, and sufficient structural and construct validity. It will facilitate the measurement of the impact of websites providing health information.

The maximal prime gaps upper bound problem is one of the major mathematical problems to date. The objective of the current research is to develop a standard which will aid in the understanding of the distribution of prime numbers. This paper presents theoretical results which originated with a researchin the subject of the maximal prime gaps. the document presents the sharpest upper bound for the maximal prime gaps ever developed. The result becomes the Supremum bound on the maximal prime gaps and subsequently culminates with the conclusive proof of the Firoozbakht's Hypothesis No 30. Firoozbakht's Hypothesis implies quite a bold conjecture concerning the maximal prime gaps. In fact it imposes one of the strongest maximal prime gaps bounds ever conjectured. Its truth implies the truth of a greater number of known prime gaps conjectures, simultaneously, the Firoozbakht's Hypothesis disproves a known heuristic argument of Granville and Maier. This paper is dedicated to a fellow mathematician, the late Farideh Firoozbakht.

Real and complex analytic functions are largely studied in the field of complex analysis and are seen as very useful tools in solving problems in mathematics, physics and engineering. Real and complex numbers are a subset of semi-structured complex numbers (a new number set created to algebraically solve division by zero). Nevertheless, the properties of analytic functions made up of semi-structured complex variables (called semi-structured complex analytic functions) is yet to be explored. This limits the range of possible problems that can be resolved using analytic functions). In this regard, the aim of this paper was to expound upon the properties of semi-structured complex analytic functions and show their application in solving engineering problems. The results of this paper included (1) developing a full set of Cauchy–Riemann Equations for the semi-structured complex -space; (2) define sufficient and necessary conditions for a semi-structured complex function to be analytic; (3) determine the relationship between semi-structured complex analytic functions, Laplace’s Equations and Poisson’s Equations; and (5) provide an example of the use of these functions.

Cannabis is the most widely cultivated, trafficked and abused illicit drug (“WHO | Cannabis,” n.d.; “World Drug Report 2020,” n.d.). In 2018, an estimated 192 million people aged 15-64 years used cannabis for nonmedical purposes globally (Degenhardt et al., 2013). The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated that, across the globe, there were more than 22·1 million people with cannabis dependence (Degenhardt et al., 2018). Moreover, the same study calculated that cannabis dependence could be accounted for 646 thousand Disability Adjusted Life Years, globally. Importantly, cannabis dependence mostly affects young adults (20-24 years), and thus has significant negative impact on the growth and productivity of not only these individuals but also to the societies and nations (Degenhardt et al., 2013). In addition to the dependence syndrome, cannabis use is associated with increased risk of psychosis, cognitive dysfunction, academic problems, and road side accidents (Volkow et al., 2014). A review showed a fairly consistent associations between cannabis use and both lower educational attainment and increased reported use of other illicit drugs (Macleod et al., 2004). In the United States, Cannabis Use Disorder (CUD) is an escalating problem in young adults by legalization (Cerdá et al., 2020) where National Survey on Drug Use and Health reported increased prevalence from 5.1% in 2015 to 5.9% in 2018 in 18-25 year olds (“2019 NSDUH Detailed Tables | CBHSQ Data,” n.d.). The psychoactive effects are due to type 1 cannabinoid receptor (CB1), the cannabinoid binding protein, that are highly expressed in the cerebellar cortex (Marcaggi, 2015). CB1 is primarily found in the molecular layer at the most abundant synapse type in the cerebellum (Marcaggi, 2015) that can shape the spike activity of cerebellar Purkinje cell (Brown et al., 2019). Moreover, granule cell to Purkinje cell synaptic transmission can trigger endocannabinoid release (Alger and Kim, 2011), which may be important for information processing by cerebellar molecular layer interneurons (Dorgans et al., 2019). This suggests that endocannabinoids could be essential to neurocognitive aspects of cerebellar function (Di Marzo et al., 2015)^,(Marcaggi, 2015)^,(Alger and Kim, 2011). Accumulating evidence also suggests cerebellar modulation of the reward circuitry and social behaviour, via direct cerebellar innervation of the ventral tegmental area (VTA) including dopamine cell bodies (A1) in the VTA (Carta et al., 2019). The VTA-dopamine (DA) signalling in the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC) (Lohani et al., 2019) play a key role in motivatedbehaviours and cognition. Cerebellar neuropathological changes can result in aberrant dopaminergic activity in the NAc and mPFC (ROGERS et al., 2011)^,(Lohani et al., 2019). Therefore, there is a critical need to determine how cerebellum modulate limbic VTA-DA signalling. Cerebellar Non-Invasive Brain Stimulation (NIBS) is postulated to be most relevant in CUD since endocannabinoids are essential to cerebellar function that includes reward-related behaviours, information processing, and cognitive control. (Di Marzo et al., 2015)^,(Marcaggi, 2015)^,(Alger and Kim, 2011). Furthermore, cerebellar NIBS can facilitate training of cognitive control in CUD during a during visual cue reactivity paradigm using a mobile virtual reality (VR) interface that can also allow remote delivery of cerebellar NIBS in conjunction with VR-based cognitive training for home-based intervention. Specifically, transcranial electrical stimulation (tES) can be translatable to low-cost (<$150) mobile devices that can be used in a low resource home-based setting (Carvalho et al., 2018).

A plenty of theories on the origin of genetic codes have been proposed so far, yet all ignored the energetic driving force, its relation to the biochemical system, and most importantly, the missing “matchmaker” between proteins and nucleic acids. Here, a new hypothesis is proposed, according to which ATP is at the origin of the primordial genetic code by driving the coevolution of the genetic code with the pristine biochemical system. This hypothesis aims to show how the genetic code was produced e.g. by photochemical reactions in a protocell that derived from a lipid vesicle enclosing various life’s building blocks (e.g. nucleotides and peptides). At extant cell, ATP is the only energetic product of photosynthesis, and is at the energetic heart of the biochemical systems. ATP could energetically form and elongate chains of both polynucleotides and polypeptides, thus acting a “matchmaker” between these two bio-polymers and eventually mediating precellular biochemical innovation from energy transformation to informatization. ATP was not the only one that could drive the formation of polynucleotides and polypeptides, but favored by precellular selection. The protocell innovated a photosynthesis system to produce ATP efficiently and regularly with the aids of proteins and RNA/DNA. The completion of permanently recording the genetic information by DNA marked the dawn of cellular life operated by Darwinian evolution. The ATP hypothesis assumes or supports the photochemical origin of life, shedding light on the origins of both photosynthetic and biochemical systems, which remains largely unknown thus far. Based on ATP hypothesis, virus (like the new coronavirus) could not be the earliest life on Earth, as it has neither biochemical systems nor lipid bilayer membrane that provided relatively isolated environment for the development of protobiochemical reactions, although it owns the genetic code of a cellular life. Virus could not be a bridge between life and non-life, but is an anti-life substance, as it depletes cellular material for its own replication, and then spreads by destroying the host cells. It can be imagined that if cellular life are completely wiped out by the virus, the complete destruction of life on Earth would be inevitable.

This paper presents Chebyshev Type inequalities for the Riemann-Liouville variable-order fractional integral operator using two synchronous functions on the set of real numbers. It is the first result of its kind in the current literature using variable-order Riemann-Liouville fractional integral operator. Some special cases for the result obtained in the paper are discussed.

In this paper we provide some bounds for the error in approximating the Riemann-Stieltjes integral $\int_{a}^{b}f (t) du (t)$ by the generalized trapezoidal rule \begin{equation*} \left[ u\left( b\right) -u\left( x\right) \right] f\left( b\right) +\left[ u\left( x\right) -u\left( a\right) \right] f\left( a\right) \end{equation*} under various assumptions for the integrand $f$ and the integrator $u$ for which the above integral exists. Applications for continuous functions of selfadjoint operators and unitary operators in Hilbert spaces are provided as well.

The manuscript presents the comprehensive integrative theory of the etiology and pathogenesis of Alzheimer’s disease - the amyloid degradation toxicity hypothesis - and describes the logic that underlies it.The analysis of amyloid biomarkers and stable-isotope label kinetics (SILK) studies suggest that AD diagnosis is associated with higher cellular uptake of beta-amyloid. Uptake of beta-amyloid by cells is needed for its cytotoxicity, so the uptake rate should correlate with the rate of neurodegeneration. Also, the initial step in forming extracellular aggregates cannot occur in the interstitial fluid due to the extremely low concentration of beta-amyloid but can occur intralysosomally. Therefore, the density of extracellular aggregates should positively correlate with the rate of cellular amyloid uptake. The model, which considers that both cytotoxicity and aggregation of beta-amyloid are defined by cellular uptake, successfully reproduces the probability distribution of AD diagnosis in the population. Cellular uptake of beta-amyloid is mediated by endocytosis. Endocytosed beta-amyloid induces lysosomal permeabilization that occurs without plasma membrane damage. Lysosomal permeabilization explains ion disturbances, such as an accumulation of intracellular calcium, caused by cell exposure to extracellular beta-amyloid. Some amyloid fragments, produced from beta-amyloid by lysosomal proteases, can form membrane channels in lysosomal membranes, which are large enough to leak cathepsins to the cytoplasm. Appearance of proteases in the cytoplasm results in necrosis and/or initiation of apoptosis. If the cell survives, the damage of lysosomes leads to autophagy failure and slow recycling of mitochondria, promoting the production of reactive oxygen species and potentiating cell damage.Considering the above, the integrative theory of AD etiology and pathogenesis can be formulated. The etiology of AD is the membrane channel formation by amyloid fragments produced in lysosomes. The pathogenesis includes lysosomal permeabilization by giant membrane channels, which leak lysosomal proteases into the cytoplasm. The correlation between the density of amyloid aggregates and the probability of AD appears because the intensity of cellular uptake defines both aggregation rates in vivo and cytotoxicity of beta-amyloid.The amyloid degradation toxicity hypothesis is the integrative theory of Alzheimer’s disease (AD). It successfully interprets multiple phenomena and paradoxes associated with AD pathobiology at various levels, from molecular and cellular to biomarkers. The hypothesis explains the limitations of currently used biomarkers of AD and proposes etiology-related parameters. These parameters could be measured in humans and become novel diagnostic and prognostic clinical tools. Based on the proposed framework, we foresee the development of effective medications to treat, stall the progression of, or prevent disease development.

The etiological agent of various viral diseases has been identified, and clinical characteristics and complications of each disease are well known. In general, a viral disease appears as acute systemic inflammatory disease, but after acute infection, some patients remain asymptomatic carriers or suffer chronic viral diseases, suggesting that the phenomena are unavoidable processes for viruses’ coexistence with their hosts as virome in microbiota of human species. Although each viral disease has been described as having different pathophysiology, the host's control systems, including immune systems, against the insults from any viral infections, have the same components in previously healthy hosts. Therefore, considering the characteristics of the life cycle of viruses being dependent on the host cell and the same immune components of the host, it is reasonable assumption that there is a common immune mechanism to respond to the insults from all viral diseases. The authors discuss on the characteristics of virus infection and unresolved issues in viral diseases and propose a rationale of early immune modulators for acute insults from viral diseases based on our clinical experiences and the protein-homeostasis-system hypothesis.

Alzheimer’s disease (AD) predominantly occurs as a late-onset form (LOAD), involving neurodegeneration and cognitive decline with progressive memory loss. Over time, risk factors and aging promote accumulation of well-known AD pathologies in oxidative stress, amyloid-beta and tau protein pathology, as well as inflammation. Homeostatic glial functions regulate and suppress these AD pathologies; however, other glial states involve increased pro-inflammatory cytokine release and further pathology accumulation. Different stresses can additionally induce cellular senescence, or an irreversible differentiation process resulting in decreased supportive functions and increased, pro-inflammatory cytokine release. While these pathophysiological underpinnings all contribute to LOAD, they require temporal and mechanistic integration. This perspective hypothesizes that when individuals have threshold senescent glia accumulation, they transition from healthy cognition into mild cognitive impairment and LOAD diagnosis. Particularly, senescent microglia are predicted to represent a final threshold required for the tau pathology burden and spreading that corresponds to sustained neurodegeneration and dementia severity. We first explore age-related decline in glia that promote increases in AD pathologies, and then discuss emerging evidence linking oxidative stress, neurons containing tau pathology, and amyloid-beta to microglia, oligodendrocyte progenitor cell, and astrocyte senescence. Our hypothesis proposes that senescent astrocytes and oligodendrocyte progenitors pressure microglia to phagocytose neurons containing tau pathology. The resulting senescent microglia would form neuritic plaques and induce paracrine senescence transitioning into a progressive clinical dementia presentation. This predictive hypothesis can potentially account for why medications used to treat LOAD fail, as previous treatments have not reduced senescent glial burden. It is also coherent with the predominant hypotheses surrounding LOAD, generates testable hypotheses about LOAD, and increases rationale in testing senolytics as targeted treatments for LOAD arrest and reversal.

I wish to suggest a physiological function for alpha-synuclein (a-syn) that has the potential to explain its role in pathology. Intraneuronal proteinaceous Lewy Bodies (LBs), the pathological hallmark of Parkinson’s disease and other synucleinopathies, consist majorly of a-syn. Ample evidence suggests that LBs are not the result of simple amyloidosis of cytosolic a-syn. Benign soluble unstructured a-syn gets converted into toxic species which preferentially accumulates in LBs. But how these aberrant a-syn molecules are produced in the cytosol, is still not clear. The present hypothesis is an effort to relate a metabolic reaction specific to neuronal function, that is, phase transition, with the pathobiology of a-syn. During high frequency stimulation, which entails rapid phase transition reactions at the presynaptic compartment, aberrant interaction of a-syn with the membrane occasionally generates toxic a-syn molecules. My conjecture is that the physiological function of a-syn is to modulate membrane fluidity by a process wherein it goes through a conformation cycle driven by a flux of energy from mitochondria. It is the range of toxic a-syn produced during aberrant phase transition reaction that is responsible for pathology, not the normal a-syn that reenters the conformation cycle, thereby, resolving the paradox of the Janus-face of a-syn.

A quantum theory of gravity is among the most pursued goals in physics. I present a definitive and direct experimental proof that refutes the widely believed hypothesis of quantum gravity. The detections of astrophysical gravitational waves (GW) are inferred from the differential oscillations of suspended mirrors of optical interferometers like the aLIGO detectors. If gravity is indeed quantized, then the average energy $\bar{E}$ in the minute oscillations of the mirrors, at a frequency $\nu$, corresponds to the absorption of an integer number $N$ gravitational quanta with total energy $E_{gw}=Nh\nu$. The coherent and coincident detections across large separations of detectors, and also the constraint of the equivalence principle, dictate that the average number of quanta $\bar{N}$ forcing the oscillations obeys $\bar{N}\gg 1$, or $1/\sqrt{\bar{N}}\ll 1$. However, the average energy $\bar{E}$ in the differential oscillations is smaller than the energy of a single quantum of GW radiation at the detected astrophysical GW frequencies. This startling finding implies that $\bar{N} <1$, which is physically impossible if gravity is quantized. This singular contradiction refutes the long-held hypothesis that gravity is quantized.

The peripheral lymphatic system plays a crucial role in the recovery mechanisms after many pathological changes, such as infection, trauma, vascular, or metabolic diseases. The lymphatic clearance of different tissues from waste products, viruses, bacteria and toxic proteins significantly contributes to the correspondent recovery processes. However, understanding of the meningeal lymphatics functions is a challenging problem. The exploration of mechanisms of lymphatic communication with brain fluids as well as the role of the lymphatic system in the brain drainage, clearance and recovery are still in its infancy. Here we review novel concepts on the anatomy and physiology of the lymphatics in the brain, which warrant a substantial revision of our knowledge about the role of lymphatics in the rehabilitation of the brain functions after neural pathologies. We discuss a new vision on how to recruit the meningeal lymphatics by the opening of blood-brain barrier as a trigger mechanism of activation of the meningeal lymphatic drainage. This leads to innovative strategies in neurorehabilitation therapy.

This article is a study on the (k,s)-Riemann-Liouville fractional integral, a generalization of the Riemann-Liouville fractional integral. Firstly, we introduce several properties of the extended integral of continuous functions. Furthermore, we make the estimation of the Box dimension of the graph of continuous functions after the extended integral. It presents that the upper Box dimension of the (k,s)-Riemann-Liouville fractional integral for any continuous functions is no more than the upper Box dimension of the functions on the unit interval I=[0,1], which indicates that the upper Box dimension of the integrand f(x) will not be increased by the σ-order (k,s)-Riemann-Liouville fractional integral ksD−σf(x) where σ&gt;0 on I. Additionally, we prove that the fractal dimension of ksD−σf(x) of one-dimensional continuous functions f(x) is still one.

Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally ab-normal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.

On March 11, 2020, the World Health Organization declared the coronavirus outbreak a pandemic. Since December 2019, the world has experienced an outbreak of coronavirus disease 2019 (COVID-19). Epidemiology, risk factors, and clinical characteristics of patients with COVID-19 have been reported but the factors affecting the immune system against COVID-19 have not been well described. In this article, we provide a novel hypothesis to describe how an increase in cellular adenosine triphosphate (c-ATP) can potentially improve the efficiency of innate and adaptive immune systems to either prevent and fight off COVID-19.

Based on the foundations of thermodynamics and the equilibrium conditions for the coexistence of two phases in a magnetic Ising-like system, we show, first, that there is a critical point where the isothermal susceptibility diverges and the specific heat may remain finite, and second, that near the critical point the entropy of the system, and therefore all free energies, do obey scaling. Although we limit ourselves to such a system, we elaborate about the possibilities of finding universality, as well as the precise values of the critical exponents using thermodynamics only.

Mammalian cells maintain the complex glycerophospholipid (GPL) class compositions of their various membranes within close limits because this is essential to their well-being or viability. Surprisingly, however it is still not understood how those compositions are maintained except that GPL synthesis and degradation closely coordinated. Here, we hypothesize that abrupt changes in the chemical activity of the individual GPL classes coordinate the synthesis and degradation, as well other homeostatic processes. A previously proposed model proposed that in cellular membranes only a limited number of “allowed” or optimal GPL glass compositions exist because they are energetically more favorable than the other compositions, i.e. they represent local free energy minima (Somerharju et al. 2009). This model, however, could not satisfactorily explain how the optimal compositions are sensed by the key homeostatic enzymes i.e., the rate-limiting synthetizing enzymes and the degrading enzymes (i.e., homeostatic phospholipases). We now propose that when the mole fraction of a GPL class exceeds an optimal one, its chemical activity abruptly increases, which (i) increases its propensity to efflux from the membrane thus making it susceptible for hydrolysis by homeostatic phospholipases, (ii) increases its potency to inhibit its own biosynthesis via a feedback mechanism, (iii) enhances its conversion to another GPL class via a novel process termed “head group remodeling” or (iv) enhances its translocation to other subcellular membranes. Accordingly, abrupt changes in the chemical activity of the individual GPL classes is proposed to regulate and coordinate those four processes maintaining GPL class homeostasis in mammalian cells.

Conventional models do not fully explain composition of the solar system – for example, the presence of p-nuclei and post-post-Fe-nuclei remains not yet understood (and is one of the great unresolved puzzles of nuclear astrophysics in general); other puzzles exist. We offer a hypothesis which can explain the appearance of non-native elements in the solar system, and a feasible scenario for its implementation. The hypothesis suggests that a nuclear-fission "event" occurred in the inner part of the solar system at the time currently defined as the birth of the system. Conventional models have never considered fission as a contributing nuclei-production mechanism. Upon examination of the existing models and factual data (presented in volumes of publications but never combined into an aggregate), we identified one plausible scenario by which a fission event (not demolishing the entire solar system) could occur: an encounter with a compact super-dense stellar "fragment" (with specific properties) and its "explosion" in fission-cascades. Such scenario also helps resolve other long-standing puzzles of the solar system. For example, it provides that the fission-produced nuclei subsequently transformed into the material that (eventually) accreted into the "rocky" objects in the system (terrestrial planets, asteroids, etc.) and enriched the pre-existed hydrogen-helium objects (the Sun and the gaseous giants) – this offers an explanation for the planets’ inner position and compositional differences within the predominantly hydrogen-helium rest of the solar system. Other implications also follow.

This study delves into the intricate relationships among the constituent elements, wave speed, and energy of both mechanical waves and electromagnetic waves. By establishing connections with the string vibration equation, a compelling revelation emerges. Upon equating the energy and constituent element mass of one wave cycle of a homogeneous string with those of a single wave cycle of electromagnetic waves, it is evident that the wave speed derived from the string vibration equation consistently matches the constant speed of light. From this, a hypothesis takes root: electromagnetic waves manifest as waves resulting from the vibration of a uniform, elongated string-like material. The phenomenon of superluminal speed further fortifies the validity of this conjecture.

Alzheimer's disease (AD) is the most common cause of dementia and affects millions of people around the world. Neuronal death in AD is initiated by the toxic action of oligomeric amyloid-β (Aβ) peptides. The formation of membrane channels by Aβ is a primary molecular action and does not require any other proteins. Channels are formed by short amyloid fragments faster and more frequently than by full-length peptides. The channel formation is dependent on an electrostatic interaction between a positively charged peptide and a negatively charged membrane. Negative membranes can be found in several locations of a cell – the inner leaflet of plasma membrane, mitochondria, and lysosomes, which all are well-known cellular targets in AD. Considering that the amyloid enters a cell by endocytosis and is exposed to lysosomal enzymes, we propose the amyloid degradation toxicity hypothesis. Endopeptidases degrade the endocytosed peptide. Produced fragments form membrane channels, which can transfer various ions (including protons) and even relatively large compounds. The neutralization of lysosomal content inactivates enzymes, which fails the whole system of recycling cellular content, including autophagy. The permeabilization of lysosomes could also lead to cell death through necrotic and apoptotic mechanisms. We discuss several mechanisms that describe how amyloid degradation products reach plasma and mitochondrial membranes, and form membrane channels. The pathogenesis of AD is discussed at various levels in a context of how the primary molecular mechanism of membrane channel formation could progress into the disease state. The discussion starts at the molecular level and extends to why the development of a disease takes years and is closely associated with aging. The proposed hypothesis offers an interpretation to several clinical observations such as the involvement of iron metabolism and an inverse association between developing Alzheimer's disease and cancer. Predictions about potential biomarkers and effectiveness of future treatments are discussed.

Dirac's Large Number Hypothesis (LNH), proposed in 1937, has captivated the scientific community with its exploration of profound correlations between cosmic and atomic scales. This hypothesis delves into the intricate interplay between the infinitesimally small and the vastly large, offering potential insights into the fundamental nature of the universe. As we continue to uncover the mysteries of the cosmos, the LNH oscillates on the precipice of scientific acceptance—neither fully validated nor entirely dismissed. In this review paper, we embark on a comprehensive journey through Dirac's LNH, shedding light on its theoretical underpinnings, its implications for universe models, and its resonance with the Anthropic Principle. We delve into the possibilities of variable gravitational constants and continuous mass creation, inviting further exploration into the intricacies of our cosmic symphony. By embracing the ongoing quest for understanding, we endeavor to unravel the profound harmonies that connect the infinitesimal with the infinite, contributing to the symphony of knowledge in theoretical physics and cosmology.

Adenine and thymine homopolymer strings of at least 8 nucleotides (AT 8+mers) were characterized in Salmonella entericasubspecies I. The motif differed between cother taxonomic classes but not between Salmonella enterica serovars. The motif in plasmids was associated with serovar. Approximately 12.3% of the S. enterica motif loci had mutations. Mutability of AT 8+mers suggests that genomes undergo frequent repair to maintain optimal gene content, and that the motif facilitates self-recognition; in addition, serovar diversity is associated with plasmid content. A theory that genome regeneration accounts for both persistence of predominant Salmonella serovars and serovar diversity provides a new framework for investigating root causes of foodborne illness.

Biophoton emission has been experimented for decades. The photo-genic origin of biophoton has also been attributed to the oxidative stress or free radical production. However, there are considerable gaps in quantitative understanding of biophoton emission. In this work, I propose an analytical hypothesis for interpreting a few patterns of steady-state biophoton emission of human, including the dependency on age, the diurnal variation, and the geometric asymmetry associated with serious asymmetrical pathological conditions. The hypothesis is based on an alternative form of energy state, termed vivo-nergy, which is associated with only metabolically active organisms that are also under neuronal control. The hypothesis projects a decrease of the vivo-nergy in human during growth beyond puberty. The hypothesis also proposes a modification of the vivo-nergy by the phases of systematic or homeostatic physiology. The hypothesis further postulates that the deviation of the physiology-modified vivo-nergy from the pre-puberty level is deteriorated by acquired organ-specific pathological conditions. A temporal differential change of vivo-nergy is hypothesized to proportionally modulate oxidative stress that functions as the physical source of biophoton emission. The resulted steady-state diffusion of the photon emitted from a photo-genic source in a human geometry simplified as a homogeneous spherical domain is modeled by photon diffusion principles incorporating an extrapolated zero-boundary condition. The age and systematic physiology combined determines the intensity of the centered physiological steady-state photo-genic source. An acquired pathology sets both the intensity and the off-center position of the pathological steady-state photo-genic source. When the age-commemorated, physiology-commanded, and pathology-controlled modifications of the steady-state photo-genetic sources are implemented in the photon diffusion model, the photon fluence rate at the surface of the human-representing spherical domain reveals the patterns on age, the temporal variation corresponding to systematic physiology, and the geometric asymmetry associated with significant asymmetric pathological condition as reported for spontaneous biophoton emission. The hypothesis, as it provides conveniences for quantitative estimation of biophoton emission patterns, will be extended in future works towards interpreting the temporal characteristics of biophoton emission under stimulation.

It is due to Littlewood that the truth of the Riemann theorem implies that of the Lindel\"{o}f conjecture. This paper aims to use the idea of Littlewood to prove the Lindel\"{o}f conjecture for the Riemann zeta function. The Lindel\"{o}f $\mu $ function at the critical line is zero, with use of the Riemann theorem for the entire Riemann zeta function, proved based on the work of Heath-Brown. Our result is given to show that the Lindel\"{o}f conjecture, connected with the proof of the moment conjecture, is true.

The primary purpose of this article is to deduce specific order estimates for the \textit{Mertens Function} $M(n)$, which facilitates us to analyze the location of zeros of the \textit{Riemann Zeta function} $\zeta(s)$. The paper also provides a brief overview about the notion of the \textit{Mertens Function} $M(n)$ and \textit{Redheffer Matrices} $\mathbb{A}_{n}$. In addition to learning about various \textit{spectral properties} of $ \mathbb{A}_{n}$, we shall also deduce the relation between these two, which, eventually would lead us to establish a necessary and sufficient condition for the \textit{Riemann Hypothesis} to hold true, as justified by \textit{Redheffer} himself. We shall also observe several numerical evidence as well as theoretical justification behind the falsity of the famous \textit{Mertens Hypothesis}, along with how researchers over the years have approached towards deriving an estimate of the smallest possible natural number $n$ for which the first such violation of the theorem occurs, utilizing numerous conjectures annotating about the order of $M(n)$. Readers who are highly motivated in pursuing research in any of the topics relevent to the contents of this paper will surely find the \texttt{References} section to be extremely resourceful.

Predicting and evaluating the vitality level of public spaces of urban design is crucial before new construction and renewal, especially for developing countries, to avoid failures like "ghost neighborhood" and reduce resource waste. However, existing assessment methods for the urban vitality are either static and ignore changes in the time dimension, or rely on historical big data and are unable to predict unbuilt projects. This study combines previous methods and crowds’ characteristics observation in public space, puts forward the crowd-frequency hypothesis and constructs an algorithm, and establishes a time-dimensional urban vitality dynamic prediction model. Taking the Rundle Mall neighborhood in Adelaide, Australia, as an example, the effec-tiveness of the prediction model was proved through on-site observation sampling comparative verification method. In addition, the decision tree model was used to conduct machine learning on the case data, and a set of algorithm programs were obtained that can directly input some basic information to obtain the urban vitality level (high-medium-low) in a certain period. It can be used as a tool to support the design and decision-making processes of urban planners and government officials, providing a low-cost way to achieve sustainable urban vitality construction of late-developing cities directly.

Given the accelerating scientific, clinical and consumer interest in highly-prevalent functional gastrointestinal disorders, appropriate therapeutic strategies are needed to address the many aspects of digestive dysfunction. Accumulating evidence for the crucifer-derived bioactive molecule, sulforaphane in upstream cellular defence mechanisms highlights its potential as a therapeutic candidate in targeting functional gastrointestinal conditions together with systemic disorders. This article catalogues the evolution of and rationale for a hypothesis that utilises multifunctional sulforaphane as the initial step in restoring the ecology of the gut ecosystem; it does this primarily by targeting the functions of intestinal epithelial cells. A growing body of work has identified the colonocyte as the driver of dysbiosis, so that targeting gut epithelial function could provide an alternative to targeting the microbes themselves for remediation of microbial dysbiosis. The hypothesis discussed herein has evolved over several years and is supported by case studies showing the application of sulforaphane in gastrointestinal disorders, related food intolerance and several systemic conditions. To our knowledge, this is the first time the effects of sulforaphane have been reported in a clinical environment where several of its key properties within the gut ecosystem appear to be related to its nutrigenomic effects on gene expression.

We present a plausible solution to the now forty seven year old paleoclimatology riddle of the so-called Faint Young Sun Paradox via the combined hypothesis of the conservation of the state of radiation balance between the Earth and Sun and that of an expanding Earth, where, in the face of a changing (increasing) Solar luminosity, the Earth would maintain steady temperatures by re-adjusting the height of its atmosphere. That is to say, depending on whether or not the radius of the solid Earth is changing, this re-adjustment of the height of the Earth’s atmosphere would mean two things — i.e.: (1) either the height increases — in which event the Earth accretes matter from its immediate surroundings (i.e., the obvious pool formed by the Solar wind) thereby increasing the mass of the Earth’s atmosphere, or: (2) the height decreases — in which event the Earth naturally expels matter from its atmosphere, thereby decreasing the effective mass of the Earth. We demonstrate that if –- as the current state of the art ITRF observations seem to indicate, namely that — the Earth’s landmass is steadily expanding globally at a paltry rate of ∼+0.45±0.05mm·yr−1, and, that the Earth’s atmosphere is to have a present radial vertical height of about one third of the Earth’s radius (∼2860km) from the Earth’s surface, then, one can (might) with relative ease, explain not only the presence of liquid water on the Earth’s surface some ∼3.20±0.70Gyr ago during the Archaean eon when the Sun was about 75% of its current luminosity, but also the present radial expansion rate of the Earth. When all is said and done, the Earth system is herein cast as an auto-self-regulating incubator where the auto-self-regulating mechanism is as a result of the Earth’s atmosphere responding by automatically re-adjusting its height.

No single evolutionary event has been identified as the cause for the final emergence of our species. I propose that a mutation on CD155 receptor gene occurred to establish a symbiosis with poliovirus, which exerted its beneficial impact via RNA dependent non-genetic transgenerational inheritance, which caused a qualitative enhancement of cognitive functions. I posit that this mutation occurred in what we call, Anatomically Modern Humans, our immediate ancestor species and that the disruption of this symbiosis causes autism spectrum disorder. Positive selection of CD155 to the extent of becoming a species defining characteristic, the chronology of autism spectrum disorder prevalence increase and continued increase, the multigenerational nature of RNA inheritance, the universal infection of humans by poliovirus and a very low associated mortality rate, and several other factors support this hypothesis. Specific genetic, epidemiological and sperm miRNA content studies are suggested to test this hypothesis.

The severe and complex COVID-19 symptoms, often needing hospital care, occur suddenly, late in the virus replication stage of SARS-CoV-2 infection. Hospitalised patients have tissue damage due to micro-clots at multiple sites. Could long-covid, also clinically variable, be a milder form caused by “nano-clots”, too small to cause detectable tissue damage? The timing and suddenness of the onset of serious disease needs an explanation. A paper reported on the first 20 children needing urgent hospital care. No child had any symptoms prior to suddenly becoming seriously ill, only one had a positive PCR test but all had positive SARS-CoV-2 antibody test. That finding indicated to me that this onset occurred at the moment of sero-conversion. An emerging viral moiety, the virion-IgG-antibody complex, has concentrations rapidly increasing, then decreasing. It is known that influenza-IgG-antibody-complex consists of many virions bound together by the antibody. It seems a reasonable step to propose that SARS-2, being a large virus and having many spike proteins, can form larger clumps of virus-IgG-antibody complexes than with influenza, the former being sufficiently large to initiate micro-clots. Therefore, my hypotheses is that the SARS-CoV-2 virion-antibody complex initiates micro-clot formation. Either before or after sero-conversion, the complex will be at too low a concentration to initiate micro-clots. To be useful, a hypothesis should be testable, provide explanations and give predictions. My presentation will give examples. I like the way that several apparently separate pieces of a jig-saw puzzle have come together to form a single picture. [I suggest that the reader scrolls down to the addenda [10,11 & 12] before reading the ICAR Poster]

The sheer number of gene variants and the extent of the observed clinical and molecular heterogeneity recorded in neuropsychiatric disorders (NPDs), could be due to the magnified downstream effects initiated by a smaller group of genomic higher order alterations in response to endogenous or environmental stress. Chromosomal common fragile sites (CFS) are functionally linked with microRNA’s, gene copy number variants (CNVs), sub-microscopic deletions and duplications of DNA, rare single-nucleotide variants (SNVs/SNPs) and small insertions/deletions (indels), as well as chromosomal translocations, gene duplications, altered methylation, microRNA and L1 transposon activity and 3-D chromosomal topology characteristics. These genomic structural features have been linked with various NPDs in mostly isolated reports, and have usually only been viewed as areas harboring potential candidate genes of interest. The suggestion to use a higher level entry point, (the ‘fragilome’ and associated features), activated by a central mechanism (‘stress’) for studying NPD genetics, has the potential to unify the existing vast number of different observations in this field. This approach may explain the continuum of gene findings distributed between affected and unaffected individuals, the clustering of NPD phenotypes and overlapping comorbidities, the extensive clinical and molecular heterogeneity and the association with certain other medical disorders.

Low nasal nitric oxide (nNO) is a typical feature in Primary Ciliary Dyskinesia (PCD). nNO is part of the PCD diagnostic algorithm due to its discriminative power against other lung diseases such cystic fibrosis (CF). However, the underlying pathomechanisms are elusive. To better understand NO dysregulation in PCD, the L-arginine/NO (Arg/NO) pathway in patients with PCD (pwPCD) and CF (pwCF) and in healthy control (HC) subjects was investigated. In a prospective, controlled study, we measured in 24 pwPCD, 25 age-matched pwCF, and 14 HC the concentrations of the NO precursors Arg and homoarginine (hArg), the arginase metabolite ornithine (Orn), the NO inhibitor asymmetric dimethylarginine (ADMA), and the major NO metabolites (nitrate, nitrite) in sputum, plasma and urine by validated methods. In comparison to HC, the sputum contents (in µmol/mg) of L-Arg (PCD 18.43 vs. CF 329.46 vs. HC 9.86, p &lt; 0.001) and of ADMA (PCD 0.055 vs. CF 0.015 vs. HC 0.010, p &lt; 0.001) were higher. In contrast, the sputum contents (in µmol/mg) of nitrate and nitrite were lower in PCD compared to HC (nitrite 4.54 vs. 9.26, p = 0.023; nitrate 12.86 vs. 40.33, p = 0.008), but higher in CF (nitrite 16.28, p &lt;0.001; nitrate 56.83, p = 0.002). The metabolite concentrations in urine and plasma were similar in all groups. The results of our study indicate that PCD, unlike CF, is associated with impaired NO synthesis in the lung, presumably due to mechano-chemical uncoupling.

How important are institutions for the development of nations? Are there any existing measures which quantify the behavior of institutions? Is there any theoretical justification for measuring their behavior? This paper introduces a framework influenced by Plato’s needs theory to provide justification for measuring the behavior of institutions. This involves introducing the humanization hypothesis which states that the behavior of institutions can be measured as they, similar to human beings, are living entities with similar hierarchical needs which are essential for their survival. The paper employs an explanatory and descriptive research design which is highly theoretical in nature.

In the current era of ‘big data’, scientists are able to quickly amass enormous amount of data in a limited number of experiments. The investigators then try to hypothesize about the root cause based on the observed trends for the predictors and the response variable. This involves identifying the discriminatory predictors that are most responsible for explaining variation in the response variable. In the current work, we investigated three related multivariate techniques: Principal Component Regression (PCR), Partial Least Squares or Projections to Latent Structures (PLS), and Orthogonal Partial Least Squares (OPLS). To perform a comparative analysis, we used a publicly available dataset for Parkinson’ disease patien ts. We first performed the analysis using a cross-validated number of principal components for the aforementioned techniques. Our results demonstrated that PLS and OPLS were better suited than PCR for identifying the discriminatory predictors. Since the X data did not exhibit a strong correlation, we also performed Multiple Linear Regression (MLR) on the dataset. A comparison of the top five discriminatory predictors identified by the four techniques showed a substantial overlap between the results obtained by PLS, OPLS, and MLR, and the three techniques exhibited a significant divergence from the variables identified by PCR. A further investigation of the data revealed that PCR could be used to identify the discriminatory variables successfully if the number of principal components in the regression model were increased. In summary, we recommend using PLS or OPLS for hypothesis generation and systemizing the selection process for principal components when using PCR.rewordexplain later why MLR can be used on a dataset with no correlation

It has been demonstrated that a decrease in cellular adenosine triphosphate (c-ATP) causes cellular dysfunction. T-cells are not an exception. One of their roles is to properly detect and eliminate cancer cells. These processes occur at the expense of ATP. Therefore, it can be concluded that a decrease in c-ATP can defect T-cell function and promote cancer evolution. In this article, we provide a hypothesis to describe the correlation between the expression of PD-1 protein on T-cells and their c-ATP levels. Moreover, we present the possible predictive factors of Anti–PD(L)-1 therapy which has not yet been determined definitely.

World Health Organization (WHO) provides the guideline for managing the Particulate Matter (PM) level because when the PM level is higher, it threats the human health. For managing PM level, the procedure for measuring PM value is needed firstly. We use Tapered Element Oscillating Microbalance (TEOM)-based PM measuring sensors because it shows higher cost-effectiveness than Beta Attenuation Monitor (BAM)-based sensor. However, TEOM-based sensor has higher probability of malfunctioning than BAM-based sensor. In this paper, we call the overall malfunction as an anomaly, and we aim to detect anomalies for the maintenance of PM measuring sensors. We propose a novel architecture for solving the above aim that named as Hypothesis Pruning Generative Adversarial Network (HP-GAN). We experimentally compare the several anomaly detection architectures to certify ours performing better.

3,4-dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (S), a major component of Lewy bodies. DOPAL potently oligomerizes S, and S oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intra-neuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with S, and vice versa, are poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intra-neuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

Cerebrospinal fluid (CSF)-contacting neurons (CSF-N) located in the surface of both brain ventricles and the central canal (cc) in the spinal cord. The cc and CSF maintain a proliferative niche for neural progenitor cells and play a vital role in development of the brain. The CSF circulates in the ventricles and the subarachnoid spaces with the CSF rhythmic flow: cardiac pulsation and respiratory fluctuation. A new concept of CSF motion may be contrary to the classical one that the direction of CSF motion may vary in direction and may be dynamic in its location. The CSF pressure may also depend on the body position. Moderate music-making has been considered a potential approach for rehabilitative and restorative therapy of brain dysfunctions. Recently, we find that the CSF-Ns are present in both the interior CFS in the cc and also exterior CSF around the surface of the spinal cord. We hypothesize that CSF-N as mechanical sensors in the spinal cord could sense motion of the spinal cord. The myodural bridge is a ligament connecting a pair of deep, upper-neck muscles to the dura mater, which envelops the arachnoid mater and contains the CSF surrounding the brain and the spinal cord. We figure out the term “CSF-static compartment” and classify CSF storage location as rostral pool and caudal pool to demonstrate our hypothesis. We presume that the somatic body movement with music-making and rehabilitation-based interventions would orchestrate the CSF motion with head movement, myodural bridge stretching and puling as well as spinal bending.

The main goal of the paper is to use a generalized proportional Riemann-Liouville fractional derivative (GPRLFD) to model BAM neural networks and to study some stability properties of the equilibrium. Initially, several properties of the GPRLFD are proved such as the fractional derivative of a squared function. Also some comparison results for GPRLFD are provided. Two types of equilibrium of the BAM model with GPRLFD are defined. In connection with the applied fractional derivative and its singularity at the initial time the Mittag-Leffler exponential stability in time of the equilibrium is introduced and studied. An example is given illustrating the meaning of the equilibrium as well as its stability properties.

The paper continues the study of efficient algorithms for the computation of zeta functions over the complex plane. We aim to apply the modifications of algorithms to the investigation of underlying fractal structures associated with the Riemann zeta function. We discuss the computational complexity and numerical aspects of the implemented algorithms based on series with binomial-like coefficients.

In this paper it is shown that mathematical description of strain, constitutive law and dynamics obtained by direct replacement of integer order derivatives with Caputo or Riemann-Liouville fractional order partial derivatives, having integral representation on finite interval, in case of a guitar string, is nonobjective. The basic idea is that different observers, using this type of descriptions, obtain different results which cannot be reconciled, i.e. transformed into each other using only formulas that link the coordinates of the same point in two fixed orthogonal reference frames and formulas that link the numbers representing the same moment of time in two different choices of the origin of time measuring. This is not an academic curiosity! It is rather a problem: which one of the obtained results is correct?

In tropical Africa, forests and savannas are the two most widespread biomes and potentially represent alternative stable states with divergent species composition. A classic, but untested, hypothesis posited by White (1983) suggests that the transition zones between forests and savannas contain a floristically impoverished assemblage with few representatives from each biome. Further, the evolutionary dimension of diversity has received limited attention, despite its importance for understanding the biogeographic history of biomes. Here, we quantify species richness and several measures of evolutionary diversity in 1° grid cells, using c. 300K occurrence records of trees and shrubs combined with biome affiliation data for 3,125 species. We find that assemblages in transition zones hold fewer woody species than assemblages in forest and savanna zones, as posited by White. However, transition zones hold more phylogenetic diversity than expected given their species richness, whether one considers forest and savanna assemblages separately or together. We also show that the Congo basin forest has low levels of phylogenetic diversity given the number of species and highlight south-eastern African savannas as a centre of savanna woody species richness and phylogenetic diversity. Regions with high phylogenetic diversity given the number of both forest and savanna species were centred around the Dahomey Gap and Cameroon, mainly in transition zones. Overall, our study shows that even if floristically impoverished, transition zones lead to unexpectedly high evolutionary diversity, suggesting they are important centres of evolutionary innovation and diversification.

Suicidal behaviour is a public health problem whose magnitude is both substantial and increasing. Since many individuals seek medical treatment following a suicide attempt, strategies aimed at reducing further attempts in this population are a valid and feasible secondary prevention approach. An evaluation of the available evidence suggests that existing treatment approaches have limited efficacy in this setting, highlighting the need for innovative approaches to suicide prevention. Existing research on the neurobiology of social pain has highlighted the importance of this phenomenon as a risk factor for suicide, and has also yielded several attractive targets for pharmacological preventive strategies. In this paper, the available evidence related to these targets is synthesized and critically evaluated. The way in which social pain is related to the “anti-suicidal” properties of recently approved treatments, such as ketamine and psilocybin, is also examined. Such strategies may be effective for the short-term reduction of suicidal ideation and behaviour in individuals who have made a suicide attempt suicide prevention, particularly in cases where social pain is identified as a contributory factor. These pharmacological approaches may be effective regardless of the presence or absence of a specific psychiatric diagnosis.

Alzheimer’s disease (AD) is a genetically complex senile neurodegeneration with unknown etiology. The first gene discovered to be mutated in early-onset AD, the amyloid precursor protein (APP), has been widely assumed as a causal factor in the disease cascade due to its generation of Aβ species. APP has an evolutionarily conserved biological role and activates a signaling program with notable similarities to integrin—a cell adhesion receptor with a wide array of functions. Intriguingly, several AD genome-wide association study (GWAS) candidate genes, including the SHARPIN locus recently reported by us and others, influence signaling of the integrin pathway. Integrins are focal adhesion regulators and serve in nervous system development, synaptic plasticity, and Tau phosphorylation. These observations suggest that the function of APP probably goes beyond Aβ generation in AD. Aging—the strongest risk factor for AD—is associated with various clock-like events in cells. For instance, neurons are continuously impacted by stochastic ‘hits’ to their genomes in aging, in the forms of DNA damage, insertion-deletions, copy-number variations (CNVs) and other types of somatic mutations. DNA damage and somatic mutations can result in neoplastic changes and cancer in mitotically active cells. However, their consequences in post-mitotic cells such as aging neurons are less defined. The current hypothesis holds that the stochastic loss of DNA sequence data at random loci in aging affects longer genes by chance more frequently. As a result, the biological processes coordinated by long genes may be more vulnerable to such random aging effects. Curiously, as shown by us and others, long genes are strongly enriched for synapse- and cell adhesion-related ontologies, more than any other biological process or cellular compartment. In addition, among various cell types, neurons possess the highest levels of long gene expression and are therefore more vulnerable to such harmful effects. The long gene vulnerability hypothesis provides a simple link between aging and the genetic landscape of AD and warrants new strategies for disease modification.

Classic mitochondrial DNA phylogenetic and phylogeographic studies on the aboriginal, historical, and extant human populations of the Canary Islands have contributed to reconstructing the origin and settlement on the islands of the pre-European colonizers. The recent use of new ancient DNA targeted enrichment and next-generation sequencing techniques on new Canary Islands samples has greatly improved these molecular results, but it has also revealed significant contamination in the islands' previous aboriginal genetic pool. Following a thorough review of these cases, new phylogeographic analysis revealed the existence of a heterogeneous aboriginal population, asymmetrically distributed across the various islands, and most likely descended from a unique main settlement. These new results and new proposed coalescent ages are compatible with a Roman-mediated arrival driven by the exploitation of the purple on the Canary Islands.

Climate change has become a major concern for developing countries given the risk that it posses on energy and food independence, and on general productivity. Despite having an energy system with low carbon intensity when compared to other Latin American countries, Colombia is already facing climate change impacts and requires urgent efforts to mitigate them. As a developing country, the challenge is bigger as policies for economic growth should be in line with the global commitment of reducing greenhouse gas emissions. With the aim of contributing to the design of climate policies, this study assesses the impact of economic development on the environment by examining the validity of the Environmental Kuznets Curve hypothesis for Colombia. Statistically validated and stable autoregressive distributed lag models are estimated for three different environmental indicators: carbon dioxide emissions, methane emissions, and ecological footprint. Moreover, the effects of other variables such as urbanization, foreign direct investment, value added of agricultural and industrial sectors, and energy use are analyzed with dynamic simulations. Empirical evidence supports a long-run equilibrium relationship among investigated variables and the existence of an inverted U-shaped EKC relationship between Gross Domestic Product (GDP) and methane emissions, and GDP and ecological footprint. Shifting to renewable energy sources and leveraging the use of cleaner technologies in agricultural and industrial sectors are found to be key for economic growth without harming the environment.

Spontaneity and its connections to mental health and wellbeing are a central issue in both theory and practice of psychodrama, and the specialized literature sometimes even associates the presence of pathology to a lack of spontaneity. This paper describes spontaneity in Moreno's theory, its assessment, its association with other measures and concepts, and scientific advances in the field. Specifically, we present results obtained with the English and Portuguese-language versions concerning its assessment. The main purpose of this work was to study the spontaneity measure (SAI-R) in a 3 first-order factors version for a Portuguese sample of 719 subjects, divided into two independent samples. The participants were aged 18 to 69. The mean age of participants was 28.5 years (SD = 7.51), and ages ranged between 18 and 69 years. Data was collected through an online platform of a Portuguese market research company. The results revealed that the 3-factor model has acceptable validity when items 1 (“Creative”) and 7 (“Euphoric”), confirming the composite reliability, the convergent validity, but not the discriminant validity. Through multigroup analysis, the model showed to be stable. Notwithstanding the need for complementary studies, including clinical samples, the SAI-R is a short and valid instrument in clinical and non-clinical contexts when evaluating spontaneity.

Physics and neuroscience share overlapping objectives, the major of which is probably the attempt to reduce the observed universe to a set of rules. The approaches are complementary, attempting to find a reduced description of the universe or of the observer, respectively. We propose here that combining the two approaches within an observer-inclusive physical scheme, bears significant advantages. In such a scheme, the same set of rules applies to the universe and its observers, and the two descriptions are entangled. We show here that analyzing special relativity in an observer-inclusive framework can resolve its contradiction with the observed non-locality of physical interactions. The contradiction is resolved by reducing the universe (including the observer) to a dynamic distribution of closed strings (“ceons”) whose vibration waves travel at c. This ceons model is consistent with general relativity, non-locality, the holographic principle and loop quantum gravity; it also eliminates Zeno’s motion paradoxes. Yet, the model entails several new empirical predictions. Finally, the ceons model suggests a fundamental physical implementation of active biological perception. Paraphrasing Torricelli, this paper suggests that we live submerged in a c of light.

Rare cardiac adverse events are reported post vaccinations. For the SARS-CoV-2 vaccines, higher numbers of these cardiac adverse events are being reported with myocarditis disproportionately occurring in younger males. The etiology of these cardiac adverse events associated with vaccines including SARS-CoV-2 is unknown. The etiology of the higher frequency of these cardiac adverse events temporally associated with SARS-CoV-2 vaccines is also unknown. This article proposes that innate immune responses to vaccines cause elevated histamine levels post vaccination; the histamine level reached may exceed the vaccinees’ histamine tolerance level for several days. This article proposes that the elevated histamine level is causative for the reported cardiac adverse events. For myocarditis reported adverse events, this article proposes that elevated histamine levels induce cardiac capillary pericyte induced vasoconstrictions followed by localized ischemia and anoxia; this is followed by the release of troponin from myocyte cells affected by anoxia. This hypothesis is supported by the temporal onset timing of adverse events reported following SARS-CoV-2 vaccinations in the United States Department of Health and Human Services Vaccine Adverse Event Reporting System (VAERS). This model applies to multiple vaccines with innate immune response histamine levels generated varying by each vaccine and incidence frequencies correlate with vaccine reactogenicity.

Splenic micronodular T-cell/histiocyte-rich large B-cell lymphoma is possibly derived from nodal T-cell/histiocyte-rich large B-cell lymphoma; however, a transition between the nodal and splenic micronodular forms has not been described to date. Of note, the only lymph nodes to be involved in association with the splenic micronodular pattern of the disease are the splenic hilar lymph nodes, and that, with partial involvement only. Kan et al, in their series of articles, have raised the possibility that corticosteroids, when prescribed prior to splenectomy, cause histopathological and functional modulations (apoptosis, necrosis, tissue shrinkage), which modify or even obscure the diagnostic morphological features. The indications for glucocorticoid therapy are either related to the suspected lymphoma, or else to other comorbidities, like asthma and autoimmune disorders. We propose that patients with the splenic, rather than nodal subset of the disease are likely to have been prescribed corticosteroids prior to histopathologic examination of the involved tissue, causing disparate morphologies in the spleen. Apoptosis, as induced by corticosteroids, is hypothesized as the major mechanism initiating the histopa-thological and functional changes in the splenic micronodular variant of our patients.