It is time to explore the impact of length of gestation and fetal health on the human lifespan.

A recently proposed principal law of lifespan (PLOSP) proposes to extend the whole human lifespan by elongating different life stages. As the preborn stage of a human being, gestation is the foundation for the healthy development of the human body. The antagonistic pleiotropy (AP) theory of aging states that there is a trade-off between early life fitness and late-life mortality. The question is whether slower development during the gestation period would be associated with a longer lifespan. Among all living creatures, the length of the gestation period is highly positively correlated to the length of the lifespan, although such a correlation is thought to be influenced by the body sizes of different species. While examining the relationship between lifespan length and body size within the same species, dogs exhibit a negative correlation between lifespans and body sizes, while there is no such correlation among domestic cats. For humans, most adverse gestational environments shorten the period of gestation, and their impacts are long-term. While many issues remain unsolved, various developmental features have been linked to the conditions during the gestation period. Given that the length of human pregnancies can vary randomly by as long as 5 weeks, it is worth investigating whether a slow steady healthy gestation over a longer period will be related to a longer and healthier lifespan. This article discusses the potential benefits, negative impacts, and challenges of the relative elongation of the gestation period.

Systems genetics of influenza A virus-infected mice identifies TRIM21 as a critical regulator of pulmonary innate immune response.

Tripartite motif 21 (TRIM21) is a cytosolic Fc receptor that targets antibody-bound, internalized pathogens for destruction. Apart from this intrinsic defense role, TRIM21 is implicated in autoimmune diseases, inflammation, and autophagy. Whether TRIM21 participates in host interactions with influenza A virus (IAV), however, is unknown. By computational modeling of body weight and lung transcriptome data from the BXD parents (C57BL/6 J (B6) and DBA/2 J (D2)) and 41 BXD mouse strains challenged by IAV, we reveal that a Trim21-associated gene network modulates the early host responses to IAV infection. Trim21 transcripts were significantly upregulated in infected mice of both B6 and D2 backgrounds. Its expression was significantly higher in infected D2 than in infected B6 early after infection and significantly correlated with body weight loss. We identified significant trans-eQTL on chromosome 14 that regulates Trim21 expression. Nr1d2 and Il3ra were among the strongest candidate genes. Pathway analysis found Trim21 to be involved in inflammation and immunity related pathways, such as inflammation signaling pathways (TNF, IL-17, and NF-κB), viral detection signaling pathways (NOD-like and RIG-I-like), influenza, and other respiratory viral infections. Knockdown of TRIM21 in human lung epithelial A549 cells significantly augmented IAV-induced expression of IFNB1, IFNL1, CCL5, CXCL10, and IFN-stimulated genes including DDX58 and IFIH1, among others. Our data suggest that a TRIM21-associated gene network is involved in several aspects of inflammation and viral detection mechanisms during IAV infection. We identify and validate TRIM21 as a critical regulator of innate immune responses to IAV in human lung epithelial cells.

The Role of Thyroid Hormone Synthesis Gene-Related miRNAs Profiling in Structural and Functional Changes of The Thyroid Gland Induced by Excess Iodine.

At recent years, the impairment caused by iodine excess are paid more attention. However, there is still largely unknown about the exact mechanism induced by excessive iodine. MiRNAs have been found to act as biomarkers for a variety of diseases, whereas fewer studies focused on miRNAs related to a cluster of genes regulating thyroid hormone synthesis, such as NIS, Pendrin, TPO, MCT8, TSHR, TSHα, and TSHß-related miRNAs in structural and functional changes of the thyroid gland induced by subchronic and chronic high iodine exposure. In the present study, one hundred and twenty 4-week-old female Wistar rats were randomly divided into control group (I50µg/L KIO3); HI 1 (I6000µg/L KIO3); HI 2 (I10000µg/L KIO3); and HI 3 (I50000µg/L KIO3), the exposure period was 3 months and 6 months, respectively. The iodine contents in the urine and blood, thyroid function, and pathological changes were determined. In addition, levels of thyroid hormone synthesis genes and the associated miRNAs profiling were detected. The results showed that subclinical hypothyroidism occurred in the high iodine groups with subchronic high iodine exposure, while 6-month exposure led to hypothyroidism in the I10000µg/L and I50000µg/L groups. Subchronic and chronic high iodine exposure caused mRNA and protein levels of NIS, TPO, and TSHR decreased significantly, and Pendrin expression increased significantly. In addition, MCT8 mRNA and protein levels are only remarkably decreased under the subchronic exposure. PCR results showed that levels of miR-200b-3p, miR-185-5p, miR-24-3p, miR-200a-3p, and miR-25-3p increased significantly exposed to high iodine for 3 months, while miR-675-5p, miR-883-5p, and miR-300-3p levels increased significantly under the exposure to high iodine for 6 months. In addition, miR-1839-3p level was markedly decreased exposed to high iodine for 3 and 6 months. Taken together, the miRNA profiling of genes regulating thyroid hormone synthesis remarkably altered from subclinical hypothyroidism to hypothyroidism induced by excess iodine exposure, and some miRNAs may play an important role in subclinical hypothyroidism or hypothyroidism through regulating NIS, Pendrin, TPO, MCT8, and TSHR providing promising targets to alleviate the impairment on the structure and function of thyroid gland.

Systems genetics and bioinformatics analyses using ESR1-correlated genes identify potential candidates underlying female bone development.

Estrogen receptor α (ESR1) is involved in E2 signaling and plays a major role in postmenopausal bone loss. However, the molecular network underlying ESR1 has not been explored. We used systems genetics and bioinformatics to identify important genes associated with Esr1 in postmenopausal bone loss. We identified ~2300 Esr1-coexpressed genes in female BXD bone femur, functional analysis of which revealed 'osteoblast signaling' as the most enriched pathway. PPI network led to the identification of 25 'female bone candidates'. The gene-regulatory analysis revealed RUNX2 as a key TF. ANKRD1 and RUNX2 were significantly different between osteoporosis patients and healthy controls. Sp7, Col1a1 and Pth1r correlated with multiple femur bone phenotypes in BXD mice. miR-3121-3p targeted Csf1, Ankrd1, Sp7 and Runx2. ß-estradiol treatment markedly increased the expression of these candidates in mouse osteoblast. Our study revealed that Esr1-correlated genes Ankrd1, Runx2, Csf1 and Sp7 may play important roles in female bone development.

Variation of sexual dimorphism and asymmetry in disease expression of inflammatory arthritis among laboratory mouse models with different genomic backgrounds.

Sex difference has shown in the arthritis diseases in human population and animal models. We investigate how the sex and symmetry vary among mouse models with different genomic backgrounds. Disease data of sex and limbs accumulated in the past more than two decades from four unique populations of murine arthritis models were analyzed. They are (1) interleukin-1 receptor antagonist (IL-1ra) deficient mice under Balb/c background (Balb/c KO); (2) Mice with collagen II induced arthritis under DBA/1 background; (3) Mice with collagen II induced arthritis under C57BL/6 (B6) background and (4) A F2 generation population created by Balb/c KO X DBA/1 KO. Our data shows that there is a great variation in sexual dimorphism for arthritis incidence and severity of arthritis in mice harboring specific genetic modifications. For a F2 population, the incidence of arthritis was 57.1% in female mice and 75.6% in male mice. There was a difference in severity related to sex in two populations: B6.DR1/ B6.DR4 (P < 0.001) and F2 (P = 0.023) There was no difference Balb/c parental strain or in collagen-induced arthritis (CIA) in DBA/1 mice. Among these populations, the right hindlimbs are significantly higher than the scores for the left hindlimbs in males (P < 0.05). However, when examining disease expression using the collagen induced arthritis model with DBA/1 mice, sex-dimorphism did not reach statistical significance, while left hindlimbs showed a tendency toward greater disease expression over the right. Sexual dimorphism in disease expression in mouse models is strain and genomic background dependent. It sets an alarm that potential variation in sexual dimorphism among different racial and ethnic groups in human populations may exist. It is important to not only include both sexes and but also pay attention to possible variations caused by disease expression and response to treatment in all the studies of arthritis in animal models and human populations.

Traditional Chinese medicine as a novel therapy for colorectal cancer by modulating intestinal flora.

Colorectal cancer is a common clinical malignant tumor of the digestive tract, and intestinal flora has played an important role in the development of colorectal cancer. Bifidobacteria, as one of the main dominant florae in intestinal tract, can inhibit the occurrence and development of colorectal cancer through various mechanisms. Recent studies have shown that traditional Chinese medicine can regulate the abundance of bifidobacteria in intestinal tract and exhibit anti-tumor effects on colorectal cancer. Detailed investigations have revealed that the mechanisms of bifidobacteria in the treatment of colorectal cancer involve three aspects: the production of short-chain fatty acids, the regulation of the body's immunity, and the regulation of cell apoptosis and differentiation. In this review, we provide an updated summary of recent advances in our understanding of the mechanisms by which traditional Chinese medicine regulate intestinal flora to inhibit colorectal cancer development and metastasis.

Time to establish an international vaccine candidate pool for potential highly infectious respiratory disease: a community's view.

In counteracting highly infectious and disruptive respiratory diseases such as COVID-19, vaccination remains the primary and safest way to prevent disease, reduce the severity of illness, and save lives. Unfortunately, vaccination is often not the first intervention deployed for a new pandemic, as it takes time to develop and test vaccines, and confirmation of safety requires a period of observation after vaccination to detect potential late-onset vaccine-associated adverse events. In the meantime, nonpharmacologic public health interventions such as mask-wearing and social distancing can provide some degree of protection. As climate change, with its environmental impacts on pathogen evolution and international mobility continue to rise, highly infectious respiratory diseases will likely emerge more frequently and their impact is expected to be substantial. How quickly a safe and efficacious vaccine can be deployed against rising infectious respiratory diseases may be the most important challenge that humanity will face in the near future. While some organizations are engaged in addressing the World Health Organization's "blueprint for priority diseases", the lack of worldwide preparedness, and the uncertainty around universal vaccine availability, remain major concerns. We therefore propose the establishment of an international candidate vaccine pool repository for potential respiratory diseases, supported by multiple stakeholders and countries that contribute facilities, technologies, and other medical and financial resources. The types and categories of candidate vaccines can be determined based on information from previous pandemics and epidemics. Each participant country or region can focus on developing one or a few vaccine types or categories, together covering most if not all possible potential infectious diseases. The safety of these vaccines can be tested using animal models. Information for effective candidates that can be potentially applied to humans will then be shared across all participants. When a new pandemic arises, these pre-selected and tested vaccines can be quickly tested in RCTs for human populations.

The mechanism underlying fluoride-induced low-renin hypertension is related to an imbalance in the circulatory and local renin-angiotensin systems.

The renin-angiotensin system (RAS) is an important fluid regulation system in the body, and excessive activation of the circulatory or local RAS can increase blood pressure (BP). Excess fluoride can increase BP, although the underlying mechanism related to activation of the RAS remains unclear. Thus, the aim of this study was to elucidate the role of the RAS in fluoride-induced hypertension. Markers of the circulating and local RASs related to pathological changes to the kidneys, myocardium, and aorta were measured. Fluoride reduced serum levels of renin, angiotensin II (Ang II), and angiotensin (1-7) [Ang (1-7)], and dysregulated plasma levels of aldosterone and potassium levels. Excess fluoride can damage the kidneys, myocardium, and aorta, overactivate the renal angiotensin converting enzyme (ACE)-Ang II-angiotensin type 1 receptor axis, and inhibit activation of the ACE2-Ang (1-7)-Mas axis, leading to dysregulation of alpha epithelial sodium channels and significantly increased expression of Ang II in the myocardium and aorta. Hence, excess fluoride can cause low-renin hypertension via an imbalance between the circulatory and local RASs.

The Value of Circulating Tumor Cells and Tumor Markers Detection in Lung Cancer Diagnosis.

OBJECTIVE: Circulating tumor cells are complete tumor cells with multi-scale analysis values that present a high potential for lung cancer diagnosis. To enhance the accuracy of lung cancer diagnosis, we detected circulating tumor cells by the innovated conical micro filter integrated microfluidic system. METHODS: We recruited 45 subjects of study, including 22 lung cancer patients, 2 precancerous patients, the control group including 14 healthy participants, and 7 patients with lung benign lesions in this prospective study. We calculated the area under the receiver operating characteristic curve of circulating tumor cells, cytokeratin19 fragment, carcinoma embryonic antigen, squamous cell carcinoma, neuron-specific enolase, and their combination, respectively, while compared the circulating tumor cells levels between vein blood and arterial blood. A conical shape filter embedded in a microfluidic chip was used to improve the detection capability of circulating tumor cells. RESULTS: The study indicated that the sensitivity, specificity, positive predictive value, and negative predictive value of circulating tumor cells detection were 81.8%, 90.5%, 90.0%, and 82.6%, respectively. The circulating tumor cells level of lung cancer patient was significantly higher than that of the control group (P < .05). The area under the curve of circulating tumor cells, cytokeratin19 fragment, carcinoma embryonic antigen, squamous cell carcinoma, and neuron-specific enolase alone was 0.838, 0.760, 0.705, 0.614, and 0.636, respectively. The combination area under the curve of the 4 tumor markers (cytokeratin19 fragment, carcinoma embryonic antigen, squamous cell carcinoma, and neuron-specific enolase) was 0.805 less than that of circulating tumor cells alone. Together, the total area under the curve of circulating tumor cell and the 4 tumor markers were 0.847, showing the highest area under the curve value among all biomarkers. In addition, this study found that there was no significant difference in positive rate of circulating tumor cell between arterial and venous blood samples. CONCLUSION: The circulating tumor cells detection technology by conical micro filter integrated microfluidic could be used for lung cancer diagnosis with high sensitivity and specificity. Complementary combination of circulating tumor cells and conventional 4 lung cancer markers could enhance the clinical application accuracy. Venous blood should be used as a routine sample for circulating tumor cells detections.

Level of Estrogen in Females-The Different Impacts at Different Life Stages.

Historically, a high level of estrogen in women is regarded as the signature for a longer lifespan than men. Estrogen is known to be responsible for the development and regulation of the female reproductive system and secondary sex characteristics. Ovariectomy brings on numerous complications such as early menopause, heart disease, and osteoporosis. Thus, ovariectomy impacts the long-term health and lifespan of women. However, the level of estrogen at different life stages should be managed differently. Life quality can be measured in many ways, but mainly it relates to how an individual is doing in terms of being healthy, comfortable, and able to participate in or enjoy life experiences. First of all, ovariectomy not only reduces the level of estrogen but also destroys the reproductive metabolism and potentially other metabolism functions; it may also reduce the lifespan because of the overall impact, not necessary due to the low level of estrogen. Secondly, according to the principal law of the lifespan (PLOSP), the impacts of ovariectomy at different life stages will be different. The objective of this article is to provide readers with a new view of the research on estrogen. Based on the PLOSP, we recapture the estrogen levels at different life stages and explore potential alternative approaches to the manipulation of the levels of estrogen based on the biological features of the difference life stages. Thus, a low level of estrogen in the early life stage may make a woman live longer than a woman with a normal level of estrogen. However, a low estrogen level does not equal ovariectomy. Here, we explain the different impacts of the estrogen levels during different life stages; the effects on the lifespan of the manipulation of estrogen levels at different life stages; and the differences among the estrogen levels, ovariectomy effects, life stages, and lifespan. The personalized manipulation of estrogen levels and relevant growth factors according to the characterization of the life stages may be able to extend the heathy lifespan of women.

A Historical Misconception in Clinical Trials of Drugs for Cancer-Age Grouping.

In clinical trials of cancer drugs, grouping by age is a very common grouping method, as it can allow for a visual comparison of the different pharmaceutical responses in patients at different age stages. Under the guidance of this thinking, many researchers use age grouping when studying clinical cancer drugs. However, even people at the same age may be at different stages in their lives, such as individuals who are going through puberty, menopause/andropause, or intermediate transition, as well as childhood and old age, affected by factors such as hormone levels, immune responses, ethnic groups, and regions. Every individual has different cancer symptoms and responses to drugs; therefore, the experimental effect of life stage grouping will be more obvious and clearer. Not only does this conclusion apply to cancer drugs, but it also applies to clinical trials for other diseases. In addition, this does not mean that age grouping should be completely abandoned. Life stage is a more general interval that can be further divided into life stage groups according to the age of the patients. Based on the principal law of lifespan (PLOSP), age trends in life stages also need to be updated from time to time. To date, life stage grouping has not been discussed systematically and has not been used as a grouping method for cancer patients. In this paper, life stage grouping is discussed as one of the important grouping categories in cancer clinical trials.

Bring the life stages into the domain of basic and clinical pharmacology.

Completely distinct physiological conditions and immune responses exist among different human life stages. Age is not always consistent with the life stage. We proposed to incorporate the concept of the life stages into basic and clinical pharmacology, including clinical trials, drug labels, and drug usage in clinical practice. Life-stage-based medical treatment is the application of medicine according to life stages such as prepuberty, reproductive, and aging. A large number of diseases are life-stage-dependent. Many medications and therapy have shown various age effects but not been recognized as life-stage-dependent. The same dosage and drug applications used in different life stages lead to divergent outcomes. Incorporating life stages in medicine and drug usage will enhance the efficacy and precision of the medication in disease treatment.

An alternative approach-combination of lockdown and open in fighting COVID-19 pandemics.

As the COVID-19 pandemic enters its third year and the omicron variant becomes dominant, we propose an alternative strategy for dealing with COVID-19, called hybrid lockdown, that is, the combination of lockdown (the centralized and organized lockdown of the high-risk population) and free mobility (normal mobility) of the low-risk population. Such an approach will enable a country or region, especially with a high population density, to achieve significant prevention and control the effects of the COVID-19 pandemic at the least cost.

Mortality in Four Waves of COVID-19 Is Differently Associated with Healthcare Capacities Affected by Economic Disparities.

BACKGROUND: The greatest challenges are imposed on the overall capacity of disease management when the cases reach the maximum in each wave of the pandemic. METHODS: The cases and deaths for the four waves of COVID-19 in 119 countries and regions (CRs) were collected. We compared the mortality across CRs where populations experience different economic and healthcare disparities. FINDINGS: Among 119 CRs, 117, 112, 111, and 55 have experienced 1, 2, 3, and 4 waves of COVID-19 disease, respectively. The average mortality rates at the disease turning point were 0.036, 0.019. 0.017, and 0.015 for the waves 1, 2, 3, and 4, respectively. Among 49 potential factors, income level, gross national income (GNI) per capita, and school enrollment are positively correlated with the mortality rates in the first wave, but negatively correlated with the rates of the rest of the waves. Their values for the first wave are 0.253, 0.346 and 0.385, respectively. The r value for waves 2, 3, and 4 are -0.310, -0.293, -0.234; -0.263, -0.284, -0.282; and -0.330, -0.394, -0.048, respectively. In high-income CRs, the mortality rates in waves 2 and 3 were 29% and 28% of that in wave 1; while in upper-middle-income CRs, the rates for waves 2 and 3 were 76% and 79% of that in wave 1. The rates in waves 2 and 3 for lower-middle-income countries were 88% and 89% of that in wave 1, and for low-income countries were 135% and 135%. Furthermore, comparison among the largest case numbers through all waves indicated that the mortalities in upper- and lower-middle-income countries is 65% more than that of the high-income countries. INTERPRETATION: Conclusions from the first wave of the COVID-19 pandemic do not apply to the following waves. The clinical outcomes in developing countries become worse along with the expansion of the pandemic.

Beta-caryophyllene prevents the defects in trabecular bone caused by Vitamin D deficiency through pathways instated by increased expression of klotho.

AIMS: This study investigated the effects of ß-caryophyllene (BCP) on protecting bone from vitamin D deficiency in mice fed on a diet either lacking (D-) or containing (D+) vitamin D. METHODS: A total of 40 female mice were assigned to four treatment groups (n = 10/group): D+ diet with propylene glycol control, D+ diet with BCP, D-deficient diet with control, and D-deficient diet with BCP. The D+ diet is a commercial basal diet, while the D-deficient diet contains 0.47% calcium, 0.3% phosphorus, and no vitamin D. All the mice were housed in conditions without ultraviolet light. Bone properties were evaluated by X-ray micro-CT. Serum levels of klotho were measured by enzyme-linked immunosorbent assay. RESULTS: Under these conditions, the D-deficient diet enhanced the length of femur and tibia bones (p < 0.050), and increased bone volume (BV; p < 0.010) and trabecular bone volume fraction (BV/TV; p < 0.010) compared to D+ diet. With a diet containing BCP, the mice exhibited higher BV and bone mineral density (BMD; p < 0.050) than control group. The trabecular and cortical bone were also affected by vitamin D and BCP. In addition, inclusion of dietary BCP improved the serum concentrations of klotho (p < 0.050). In mice, klotho regulates the expression level of cannabinoid type 2 receptor (Cnr2) and fibroblast growth factor 23 (Fgf23) through CD300a. In humans, data suggest that klotho is connected to BMD. The expression of klotho is also associated with bone markers. CONCLUSION: These data indicate that BCP enhances the serum level of klotho, leading to improved bone properties and mineralization in an experimental mouse model.Cite this article: Bone Joint Res 2022;11(8):528-540.

Potential Similarities in Sex Difference in Key Genes and Their Expression, Network, EQTL and Pathways between COVID-19 and Chronic Kidney Disease Based on Mouse Model.

COVID-19 and chronic kidney disease (CKD) share similarity in sex bias and key genes in the disease pathway of sex difference. We investigated the sex difference of molecular pathways of four key players of these two diseases using an existing large set of whole genome expression profiles from the kidneys of female and male mouse models. Our data show that there is little to no correlation at the whole genome expression level between female and male mice among these four genes. There are considerable sex differences among genes in upstream regulation, Ace2 complex interaction, and downstream pathways. Snap25 and Plcb4 may play important roles in the regulation of the expression level of Adam17, Tmprss2, and Cd146 in females. In males, Adh4 is a candidate gene for the regulation of Adam17, while Asl, Auts2, and Rabger1 are candidates for Tmprss2. Within the Ace2 complex, Cd146 directly influences the expression level of Adam17 and Ace2 in the female, while in the male Adam potentially has a stronger influence on Ace2 than that of Tmprss2. Among the top 100 most related genes, only one or two genes from four key genes and 11 from the control B-Actin were found to be the same between sexes. Among the top 10 sets of genes in the downstream pathway of Ace2, only two sets are the same between the sexes. We concluded that these known key genes and novel genes in CKD may play significant roles in the sex difference in the CKD and COVID-19 disease pathways.

Healthy Long-Lived Human Beings-Working on Life Stages to Break the Limitation of Human Lifespans.

The human lifespan has been increasing but will soon reach a plateau. A new direction based on the principal law of lifespan (PLOSP) may enable the human lifespan to be extremely healthy and long by the proper manipulation of the well-defined growing stages of the lifespan. The lifespan of creatures on earth from a single cell to animals can be elongated at different life stages including prenatal development, body growth, reproductivity, and aging. Each life stage has its own specific physiological and metabolic characteristics. Each life stage can be lengthened by either slowing its processes or continuously maintaining the activities of its function. Unfortunately, the current biomedical research on the extension of lifespans has mainly focused on the aging stage. Recognizing and clearly defining the periods of transition and the boundaries of life stages are essential for achieving the goal of long-lived healthy humans based on the PLOSP. The biomedical measures and pharmacological treatments for the extension of lifespans is life-stage-specific. The PLOSP can be tested with modified studies on longevity with a variety of technologies such as castration and ovariectomy. Sex differences in biological functions and the sequential order of the life stages requires different approaches for females and males.