Authors and Reviewers
Articles in press have been peer-reviewed and accepted, which are not yet assigned to volumes /issues, but are citable by Digital Object Identifier (DOI).
Obesity is an escalating global pandemic posing a serious threat to human health. The intervention therapy using weight-reducing drugs, accompanied by lifestyle modification, is a strategy for the treatment of obesity. In the present study, we explored the role of fucoidan, a seaweed compound, on high-fat diet (HFD)-induced obesity in mice. We found that fucoidan treatment significantly reduced the body fat and caused redistribution of visceral and subcutaneous fat in HFD-fed mice. Meanwhile, fucoidan treatment inhibited adipocyte hypertrophy and inflammation in adipose tissue. Collectively, these results suggest that fucoidan may be a promising treatment for obesity and obesity-induced complications.
Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people. Nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS) in the brain. Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders, including stroke, depression and anxiety disorders, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, chronic pain, and drug addiction. Due to critical roles of nNOS in learning and memory and synaptic plasticity, direct inhibition of nNOS may cause severe side effects. Importantly, interactions of several proteins, including post-synaptic density 95 (PSD-95), carboxy-terminal PDZ ligand of nNOS (CAPON) and serotonin transporter (SERT), with the PSD/Disc-large/ZO-1 homologous (PDZ) domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain. Therefore, it will be a preferable means to interfere with nNOS-mediated protein-protein interactions (PPIs), which do not lead to undesirable effects. Herein, we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders, and the discovery of drugs targeting the PPIs, which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.
There are an estimated 10 000 monogenic diseases affecting tens of millions of individuals worldwide. The application of CRISPR/Cas genome editing tools to treat monogenic diseases is an emerging strategy with the potential to generate personalized treatment approaches for these patients. CRISPR/Cas-based systems are programmable and sequence-specific genome editing tools with the capacity to generate base pair resolution manipulations to DNA or RNA. The complexity of genomic insults resulting in heritable disease requires patient-specific genome editing strategies with consideration of DNA repair pathways, and CRISPR/Cas systems of different types, species, and those with additional enzymatic capacity and/or delivery methods. In this review we aim to discuss broad and multifaceted therapeutic applications of CRISPR/Cas gene editing systems including in harnessing of homology directed repair, non-homologous end joining, microhomology-mediated end joining, and base editing to permanently correct diverse monogenic diseases.
With advancements in gene editing technologies, our ability to make precise and efficient modifications to the genome is increasing at a remarkable rate, paving the way for scientists and clinicians to uniquely treat a multitude of previously irremediable diseases. CRISPR-Cas9, short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9, is a gene editing platform with the ability to alter the nucleotide sequence of the genome in living cells. This technology is increasing the number and pace at which new gene editing treatments for genetic disorders are moving toward the clinic. The β-hemoglobinopathies are a group of monogenic diseases, which despite their high prevalence and chronic debilitating nature, continue to have few therapeutic options available. In this review, we will discuss our existing comprehension of the genetics and current state of treatment for β-hemoglobinopathies, consider potential genome editing therapeutic strategies, and provide an overview of the current state of clinical trials using CRISPR-Cas9 gene editing.
Colorectal cancer (CRC) is one of the most deadly cancers in the world with few reliable biomarkers that have been selected into clinical guidelines for prognosis of CRC patients. In this study, mRNA microarray datasets GSE113513, GSE21510, GSE44076, and GSE32323 were obtained from the Gene Expression Omnibus (GEO) and analyzed with bioinformatics to identify hub genes in CRC development. Differentially expressed genes (DEGs) were analyzed using the GEO2R tool. Gene ontology (GO) and KEGG analyses were performed through the DAVID database. STRING database and Cytoscape software were used to construct a protein-protein interaction (PPI) network and identify key modules and hub genes. Survival analyses of the DEGs were performed on GEPIA database. The Connectivity Map database was used to screen potential drugs. A total of 865 DEGs were identified, including 374 upregulated and 491 downregulated genes. These DEGs were mainly associated with metabolic pathways, pathways in cancer, cell cycle and so on. The PPI network was identified with 863 nodes and 5817 edges. Survival analysis revealed that HMMR, PAICS, ETFDH, and SCG2 were significantly associated with overall survival of CRC patients. And blebbistatin and sulconazole were identified as candidate drugs. In conclusion, our study found four hub genes involved in CRC, which may provide novel potential biomarkers for CRC prognosis, and two potential candidate drugs for CRC.
Protein ubiquitination is essential for diverse cellular functions including spermatogenesis. The tripartite motif (TRIM) family proteins, most of which have E3 ubiquitin ligase activity, are highly conserved in mammals. They are involved in important cellular processes such as embryonic development, immunity, and fertility. Our previous studies indicated that Trim69, a testis-specific expressed TRIM family gene, potentially participates in the spermatogenesis by mediating testicular cells apoptosis. In this study, we investigated the biological functions of Trim69 in male mice by established Trim69 knockout mice with CRISPR/Cas9 genomic editing technology. Here, we reported that the male Trim69 knockout mice had normal fertility. The adult knockout mice have shown that the appearance of testes, testis/body weight ratios, testicular histomorphology, and the number and quality of sperm were consistent with wild-type mice. These results indicated that the E3 ubiquitin ligase protein Trim69 was not essential for male mouse fertility, and it might be compensated by other TRIM family members such as Trim58 in Trim69-deficiency testis. This study would help to elucidate the functions of tripartite motif protein family and the regulation of spermatogenesis.
To evaluate if valproic acid (VPA) therapy is associated with vitamin D deficiency among infants and toddlers with epilepsy, a cross-sectional clinical study was conducted in 25 children with epilepsy taking VPA. Blood levels of calcium, phosphorus, alkaline phosphatase, and 25-hydroxy vitamin D [25(OH)D] and plasma VPA level were measured at 1- to 3-month intervals. At the initial and final measurements, vitamin D deficiency or insufficiency was recognized in 8 (32%) and 12 (42%), respectively. In girls, a decreasing trend in serum 25(OH)D levels (P<0.05) was observed. Polytherapy had a significant negative effect on the longitudinal change of 25(OH)D (P<0.05) in girls. In conclusion, our study indicates that a high proportion of girls after VPA therapy had hypovitaminosis D.
Previous studies have demonstrated that Chinese lung adenocarcinoma (LUAD) patients have unique genetic characteristics, however, the specific genomic features relating to the development and treatment of LUAD in the Chinese population are not fully understood. Here, we applied the ultra-deep targeted sequencing to 66 Chinese LUAD samples, accompanied by comparative analysis with 162 Caucasian LUAD in The Cancer Genome Atlas. We focused on the 68 recurrently mutated genes and results revealed that the panel-based tumor mutational burden (pTMB) is significantly higher in the Chinese LUAD (P=0.0017). Additionally, the percentage of smoking-associated C>A transversion is significantly lower in Chinese LUAD (15.5%vs. 39.7%, P=5.69×10−27), while C>T transition is more frequent in Chinese LUAD (35.8%vs. 25.7%, P=2.67×10−5), which indicated the ethnic difference in mutation types. Notably, novel driver genes (GNAS and JAK1) that are peculiar to Chinese LUAD were identified, and a more convergent distribution of mutations was observed in the Chinese cohort (P=0.012) compared with scattered mutations in Caucasian LUAD. Our results present a distinct genomic profile of Chinese LUAD compared to Caucasians LUAD and elucidate the ethnic difference in mutation distribution besides the type and rate.
After type A acute aortic dissection (AAD) repair or modified Bentall procedure, uncontrollable bleeding from the anastomotic sites of the fragile dissected tissues or aortic root area is a critical situation to a cardiac surgeon. For postoperative care, lots of blood transfusion with strict monitoring on the patient all night and subsequent reoperation for the bleeding control is usually needed. We managed to make contained local compression of upper half of the heart, from upper part of the right ventricle to just above the innominate vein, using bovine pericardium with closing both sides of transverse sinus in two cases of uncontrolled postoperative bleeding (bleeding from distal anastomotic site in type-A AAD and valve sitting site in modified Bentall procedure). Even though reoperations for the removal of packed gauges were done in both cases 2 days later, postoperative courses at intensive care unit were very smooth with little need for transfusion. This kind of contained local compression trial could be a useful strategy for dealing with the malignant uncontrollable bleeding from the fragile aortic tissue or root area after acute dissection or aortic root repair.
Mechanotransduction, a conversion of mechanical forces into biochemical signals, is essential for human development and physiology. It is observable at all levels ranging from the whole body, organs, tissues, organelles down to molecules. Dysregulation results in various diseases such as muscular dystrophies, hypertension-induced vascular and cardiac hypertrophy, altered bone repair and cell deaths. Since mechanotransduction occurs at nanoscale, nanosciences and applied nanotechnology are powerful for studying molecular mechanisms and pathways of mechanotransduction. Atomic force microscopy, magnetic and optical tweezers are commonly used for force measurement and manipulation at the single molecular level. Force is also used to control cells, topographically and mechanically by specific types of nano materials for tissue engineering. Mechanotransduction research will become increasingly important as a sub-discipline under nanomedicine. Here we review nanotechnology approaches using force measurements and manipulations at the molecular and cellular levels during mechanotransduction, which has been increasingly play important role in the advancement of nanomedicine.
Postdural puncture headache (PDPH) is an incapacitating complication that can occur following spinal anesthesia and with inadvertent dural puncture during epidural anesthesia. We present a case of a 32-year-old G2P1 female who was admitted for induction of labor and received epidural catheter placement for analgesia. After an inadvertent dural puncture and development of a PDPH, the patient was offered conservative measures for the first 48 hours without improvement. An epidural blood patch (EBP) was placed achieving only moderate relief. Two days later, a second EBP was performed and the patient developed severe back pain which radiated bilaterally to her buttocks. Magnetic resonance imaging (MRI) demonstrated the presence of blood in the intrathecal space. This could be the cause of sacral radiculitis, an uncommon complication of an EBP. This suggests that EBPs could potentially cause neurologic symptoms which may be more common than people previously thought. As complicated outcomes have followed both conservative and aggressive management, MRI can be an early diagnostic tool in such cases and a multidisciplinary approach should be taken.
Arrhythmias are very common in healthy population as well as patients with cardiovascular diseases. Among them, atrial fibrillation (AF) and malignant ventricular arrhythmias are usually associated with some clinical events. Early diagnosis of arrhythmias, particularly AF and ventricular arrhythmias, is very important for the treatment and prognosis of patients. Holter is a gold standard commonly recommended for noninvasive detection of paroxysmal arrhythmia. However, it has some shortcomings such as fixed detection timings, delayed report and inability of remote real-time detection. To deal with such problems, we designed and applied a new wearable 72-hour triple-lead H3-ECG device with a remote cloud-based ECG platform and an expert-supporting system. In this study, 31 patients were recruited and 24-hour synchronous ECG data by H3-ECG and Holter were recorded. In H3-ECG group, the ECG signals were transmitted using remote real-time modes, and confirmed reports were made by doctors in the remote expert-supporting system, while the traditional modes and detection systems were used in Holter group. The results showed no significant differences between the two groups in 24-hour total heart rate (HR), averaged HR, maximum HR, minimum HR, premature atrial complexes (PACs) and premature ventricular complexes (PVCs) (P > 0.05). The sensitivity and specificity of capture and remote automatic cardiac events detection of PACs, PVCs, and AF by H3-ECG were 93% and 99%, 98% and 99%, 94% and 98%, respectively. Therefore, the long-term limb triple-lead H3-ECG device can be utilized for domiciliary ECG self-monitoring and remote management of patients with common arrhythmia under medical supervision.
There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene expression. However, the role of metabolites in activating the key gene regulatory network for specialization of germ cell lineage remains largely unknown. Here, we identified some cellular metabolites with significant changes by untargeted metabolomics between mouse epiblast-like cells (EpiLCs) and primordial germ cell-like cells (PGCLCs). More importantly, we found that inhibition of glutaminolysis by bis-2- (5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) impeded PGCLC specialization, but the impediment could be rescued by addition of α-ketoglutarate (αKG), the intermediate metabolite of oxidative phosphorylation and glutaminolysis. Moreover, adding αKG alone to the PGCLC medium accelerated the PGCLC specialization through promoting H3K27me3 demethylation. Thus, our study reveals the importance of metabolite αKG in the germ cell fate determination and highlights the essential role of cellular metabolism in shaping the cell identities through epigenetic events.
Genome editing has undergone rapid development in recent years, yielding new approaches to make precise changes in genes. In this review, we discuss the development of various adenine and cytosine base-editing technologies, which share the ability to make specific base changes at specific sites in the genome. We also describe multiple applications of base editing in vitro and in vivo. Finally, as a practical example, we demonstrate the use of a cytosine base editor and an adenine base editor in human cells to introduce and then correct a prevalent mutation responsible for hereditary tyrosinemia type 1.
The rabbit has been recognized as a valuable model in various biomedical and biological research fields because of its intermediate size and phylogenetic proximity to primates. However, the technology for precise genome manipulations in rabbit has been stalled for decades, severely limiting its applications in biomedical research. Novel genome editing technologies, especially CRISPR/Cas9, have remarkably enhanced precise genome manipulation in rabbits, and shown their superiority and promise for generating rabbit models of human genetic diseases. In this review, we summarize the brief history of transgenic rabbit technology and the development of novel genome editing technologies in rabbits.
Accurate targeting of vesicular acetylcholine transporter (VAChT) to synaptic vesicles (SVs) is indispensable for efficient cholinergic transmission. Previous studies have suggested that the dileucine motif within the C-terminus of the transporter is sufficient for its targeting to SVs. However, the cytosolic mechanism underlying specific regulation of VAChT trafficking and targeting to SVs is still unclear. Here we use the C-terminus of VAChT as bait in a yeast-two-hybrid screen to identify sorting nexin 5 (SNX5) as its novel interacting protein. SNX5 is detected in the SVs enriched LP2 subcellular fraction of rat brain homogenate and shows strong colocalization with VAChT in both brain sections and PC12 cells. Binding assays suggest that the C-terminal domain of VAChT can interact with both BAR and PX domain of SNX5. Depletion of SNX5 enhances the degradation of VAChT and the process is mediated through the lysosomal pathway. More importantly, we find that, in PC12 cells, the depletion of SNX5 expression significantly decreases the synaptic vesicle-like vesicles (SVLVs) localization of VAChT. Therefore, the results suggest that SNX5 is a novel regulator for both stability and SV targeting of VAChT.
The Journal of Biomedical Research--2020, 34(6)
J Biomed Res 2020, 34(6): 395-396.
doi: 10.7555/JBR.34.20200701
This special issue of The Journal of Biomedical Research presents rigorous empirical analysis related to COVID-19 research in responding to the current global COVID-19 pandemic. Selected articles from different disciplines not only offer broader perspectives on combating the outbreaks, but also disseminate the most updated findings on this new challenge for human being to the field.
J Biomed Res 2020, 34(6): 397-409.
doi: 10.7555/JBR.34.20200112
The Balanced Budget Act of 1997 created a designation for critical access hospitals (CAHs) to sustain care for people living in rural communities who lacked access to care due to hospital closures over the preceding decade. Twenty-five years later, 1350 CAHs serve approximately 18% of the US population and a systematic policy evaluation has yet to be performed. This policy analysis serves to define challenges faced by CAHs through a literature review addressing the four major categories of payment, quality, access to capital, and workforce. Additionally, this analysis describes how current challenges to maintain sustainability of CAHs over time are accentuated by gaps in public health infrastructure and variability in individual health care plans exhibited during the COVID-19 pandemic.
J Biomed Res 2020, 34(6): 410-415.
doi: 10.7555/JBR.34.20200134
Measuring virus-specific antibody responses to emerging pathogens is a well-established and highly useful tool to diagnose such infections, understand interactions between the immune system and pathogens, and provide potential clues for the development of vaccines or therapeutic agents against such pathogens. Since the beginning of 2020, the discovery of SARS-CoV-2 as the emerging virus responsible for the COVID-19 pandemic has provided new insight into the complexity of antibody responses to this dangerous virus. The current review aims to sort out diverse and sometimes seemingly confusing findings to put together a cohesive understanding on the profile of antibody responses elicited in COVID-19 patients.
J Biomed Res 2020, 34(6): 416-421.
doi: 10.7555/JBR.34.20200118
The start of the global pandemic secondary to the novel SARS-CoV-2 virus was a time of uncertainty and fear as it claimed the lives of many across the world. Since then, there has been a plethora of research designs and trials in order to understand what we can do to stop the spread of the disease. Scientists and health care providers have utilized old medications and revamped them for current use such a convalescent plasma and steroids, as well as creating novel therapeutics, some with promising results. In this article, we review the major therapeutic options currently available and look into what the future still holds in order to further our understanding of this mysterious disease.
J Biomed Res 2020, 34(6): 422-430.
doi: 10.7555/JBR.34.20200119
The outbreak and rapid spread of COVID-19 has become a public health emergency of international concern. A number of studies have used modeling techniques and developed dynamic models to estimate the epidemiological parameters, explore and project the trends of the COVID-19, and assess the effects of intervention or control measures. We identified 63 studies and summarized the three aspects of these studies: epidemiological parameters estimation, trend prediction, and control measure evaluation. Despite the discrepancy between the predictions and the actuals, the dynamic model has made great contributions in the above three aspects. The most important role of dynamic models is exploring possibilities rather than making strong predictions about longer-term disease dynamics.
J Biomed Res 2020, 34(6): 431-436.
doi: 10.7555/JBR.34.20200110
We sought to determine the characteristics of viral specimens associated with fatal cases, asymptomatic cases and non-fatal symptomatic cases of COVID-19. This included the analysis of 1264 specimens found reactive for at least two SARS-CoV-2 specific loci from people screened for infection in Northern Nevada in March-May of 2020. Of these, 30 were specimens from fatal cases, while 23 were from positive, asymptomatic cases. We assessed the relative amounts of SARS-CoV-2 RNA from sample swabs by real-time PCR and use of the threshold crossing value (Ct). Moreover, we compared the amount of human RNase P found on the same swabs. A considerably higher viral load was found to be associated with swabs from cases involving fatality and the difference was found to be strongly statistically significant. Noting this difference, we sought to assess whether any genetic correlation could be found in association with virus from fatal cases using whole genome sequencing. While no common genetic elements were discerned, one branch of epidemiologically linked fatal cases did have two point mutations, which no other of 156 sequenced cases from northern Nevada had. The mutations caused amino acid changes in the 3′-5′ exonuclease protein, and the product of the gene, orf8.
J Biomed Res 2020, 34(6): 437-445.
doi: 10.7555/JBR.34.20200129
Many studies have investigated causes of COVID-19 and explored safety measures for preventing COVID-19 infections. Unfortunately, these studies fell short to address disparities in health status and resources among decentralized communities in the United States. In this study, we utilized an advanced modeling technique to examine complex associations of county-level health factors with COVID-19 mortality for all 3141 counties in the United States. Our results indicated that counties with more uninsured people, more housing problems, more urbanized areas, and longer commute are more likely to have higher COVID-19 mortality. Based on the nationwide population-based data, this study also echoed prior research that used local data, and confirmed that county-level sociodemographic factors, such as more Black, Hispanic, and older subpopulations, are attributed to high risk of COVID-19 mortality. We hope that these findings will help set up priorities on high risk communities and subpopulations in future for fighting the novel virus.
We compared subgroup differences in COVID-19 case and mortality and investigated factors associated with case and mortality rate (MR) measured at the county level in Mississippi. Findings were based on data published by the Mississippi State Department of Health between March 11 and July 16, 2020. The COVID-19 case rate and case fatality rate (CFR) differed by gender and race, while MR only differed by race. Residents aged 80 years or older and those who live in a non-metro area had a higher case rate, CFR, and MR. After controlling for selected factors, researchers found that the percent of residents who are obese, low income, or with certain chronic conditions were associated with the county COVID-19 case rate, CFR, and/or MR, though some were negatively related. The findings may help the state to identify counties with higher COVID-19 case rate, CFR, and MR based on county demographics and the degree of its chronic conditions.
Global prevalence of coronavirus disease 2019 (COVID-19) calls for an urgent development of anti-viral regime. Compared with the development of new drugs, drug repurposing can significantly reduce the cost, time, and safety risks. Given the fact that coronavirus harnesses spike protein to invade host cells through angiotensin-converting enzyme 2 (ACE2), hence we see if any previous anti-virtual compounds can block spike-ACE2 interaction and inhibit the virus entry. The results of molecular docking and molecular dynamic simulations revealed that remdesivir exhibits better than expected anti-viral invasion potential against COVID-19 among the three types of compounds including remdesivir, tenofovir and lopinavir. In addition, a positive correlation between the surface area occupied by remdesivir and anti-viral invasion potential was also found. As such, the structure of remdesivir was modified by linking an N-benzyl substituted diamidine derivative to its hydroxyl group through an ester bond. It was found that this compound has a higher anti-viral invasion potential and greater specificity.
J Biomed Res 2020, 34(6): 470-474.
doi: 10.7555/JBR.34.20200099
The ongoing coronavirus disease 2019 (COVID-19) pandemic is a global public health crisis, causing social and economic disasters in many countries. In China, two-consecutive negative results of nucleic acid tests for SARS-CoV-2 from the respiratory samples are required to end the quarantine of COVID-19 patients. However, clinicians face a dilemma in case of patients with long-term viral shedding. This report described an unusual COVID-19 case who had persistent viral RNA positivity for more than 4 months after initial illness in the presence of low neutralizing antibodies, but without prolonged clinical symptoms. Multiple anti-viral drug treatments had no impact and there was no evidence of re-infection. When the patient was self-quarantined at home, no infection occurred to the three family members living with her for 15 to 19 days. Sputum viral culture in BSL-3 laboratory on the 102nd day after symptom onset was negative. From the 129th day on, 8 continuous nucleic acid tests of sputum samples showed negative results. The patient was discharged on 137th days since symptom onset. In conclusion, viral RNA shedding in the sputum of the COVID-19 patient may last over 4 months. As no evidence shows the existence of infectious virus, two-consecutive negative nucleic acid tests may not be the prerequisite for ending quarantine of COVID-19 patients with prolonged viral shedding.
2015, 29(1): 3-19.
doi: 10.7555/JBR. 29.20140151
2017, 31(5): 386-394.
doi: 10.7555/JBR.30.20150162
2018, 32(5): 317-326.
doi: 10.7555/JBR.31.20160168
2015, 29(4): 264-284.
doi: 10.7555/JBR.29.20150035
2015, 29(4): 285-297.
doi: 10.7555/JBR.29.20140007
2016, 30(1): 19-31.
doi: 10.7555/JBR.30.20150100
2014, 28(2): 81-97.
doi: 10.7555/JBR.27.20120136
2014, 28(5): 388-395.
doi: 10.7555/JBR.28.20140015
2013, 27(1): 1-13.
doi: 10.7555/JBR.27.20120077
2013, 27(2): 85-102.
doi: 10.7555/JBR.27.20120064
2011, 25(6): 418-424.
doi: 10.1016/S1674-8301(11)60055-9
Authors and Reviewers
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