1Department of Neuroscience and Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
2Addiction Research Unit, Osaka Psychiatric Research Center, Osaka Psychiatric Medical Center, Osaka, Japan
As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied. The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle. In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms. Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis. In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation.
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**Comment**
Lyme/MSIDS also causes peripheral nervous system inflammation. Once borrelia enter the cerebrospinal fluid (CSF), they elicit an inflammatory response. This study states about 15% of patients with Lyme disease develop peripheral and central nervous system involvement, although I suspect it’s much, much higher. It also states inflammation plays a causal role in the array of neurologic changes associated with Lyme disease.
Uptick: UWSP researchers use DNA to link Lyme disease, infected ticks
May 26, 2022
Diane Caporale has collected thousands of ticks during her career as a biology professor and researcher. Since moving to Wisconsin 1999, she has had help. Nearly 500 students in her molecular biology courses at UW-Stevens Point have collected ticks each year from 2000-2020.
Tick surveillance is useful for predicting human disease risk. What’s especially significant about Caporale’s research is its duration. This is the first continuous surveillance of tick-borne pathogens for two decades in the nation. “It’s been quite an enormous, exciting project,” she said.
“It was started in 2000 — before I was born — so it’s kind of crazy the amount of time this has been going on,” said Cody Korth, a student researcher in her lab.
Caporale first began collecting ticks in the Northeast, where she grew up.
When she was asked to develop a molecular biology course at UW-Stevens Point, it was an opportunity to broaden her research into tick-borne diseases. During the first week of October each year since 2000, her molecular biology students collect blacklegged ticks (Ixodes scapularis). It gives students the opportunity to use DNA as a tool to forecast the incidence of disease.
Blacklegged (or deer) ticks carry three pathogens that can cause human disease. Caporale’s students analyzed all three: Borrelia burgdorferi, the bacterium responsible for Lyme disease; Anaplasma phagocytophilum, a bacterium that causes Anaplasmosis; and Babesia microti, a protozoan that causes Babesiosis. The latter presents with malaria-like symptoms, while the others have flu-like symptoms.
Caporale and her students conducted research in what is known as a microgeographic region that is also convenient to campus: the Schmeeckle Reserve trail around Lake Joanis. They use white flannel flags to collect the ticks – a total of 2,008 in 21 years.
The students extracted DNA and analyzed it for the presence of three pathogens that cause human diseases, then sequenced the DNA to learn what percentage of ticks were infected with one, two or all three pathogens, said McKenzi Fernholz, who took molecular biology in 2019.
Cody Korth and McKenzi Fernholz are student researchers in Biology Professor Diane Caporale’s lab at UW-Stevens Point, analyzing 20 years of data on ticks.
They found each pathogen became more prevalent over time. In 2000, Borrelia burgdorferi, which causes Lyme disease, was found in just the northwest segment of the trail. Seven years later, it reached detectable levels around the perimeter of the lake. The number of ticks with Borrelia peaked in 2015, which was also a year when a high number of ticks were infected with more than one pathogen.
Anaplasma was first detected in 2004 in the southeast segment. It reached detectable levels all around the lake within four years. Babesia was first detected in 2007 in the southwest region. It took eight years to reach detectable levels around the lake.
The highest number of infected ticks – 56% — was recorded in 2014.
An increase in the number of infected ticks in one year was related to an increase in tick-borne illness, notably Lyme disease, the following year, Korth said. The students compared their data with human disease statistics from Portage County and state public health units.
“If it’s increasing here, it’s increasing elsewhere,” said Caporale, who has also researched ticks in the Kettle Moraine area, Colfax and Whitewater. Overall, cases of Lyme disease oscillate, she said.
Caporale’s students also monitored rainfall each June, average winter temperature in December through February and snow depth for conditions that favor ticks. More eggs hatched when rainfall was higher the prior year, and more snow increased the chance of winter survival, Caporale said.
Tick numbers around Lake Joanis dropped significantly in 2017. That summer, strong winds downed numerous trees on the north end of the trail. When trees were removed, so was refuge for white-footed mice, the main reservoir for these pathogens. Also, invasive buckthorn – a preferred vegetation for ticks – was removed or treated with herbicide. In fall 2021 no ticks were found along the lake trail where extensive restoration occurred. Students did find ticks around the Schmeeckle Reserve Visitor Center carrying Borrelia and Anaplasma.
As independent study researchers in Caporale’s lab, Fernholz and Korth analyzed all the sequenced DNA data collected over the 21 years and determined trends in tick infection rates. They developed graphs and charts to display the results and presented them at the College of Letters and Science research symposium earlier this month. The results will be submitted for publication this summer.
It’s interesting to observe the correlation between infection rates in ticks and humans, Korth said, which means that tick surveillance may be able to predict Lyme disease trends in the following year. “It’s worth the time to take the samples every year because when we compared our tick infection rates to the cases of Lyme disease in humans in Portage County, we saw a one-year difference consistently with pathogen emergence.”
Korth, a biochemistry major from Marshfield, enjoys doing research independently in the lab and said it’s helped him develop critical thinking and problem-solving skills outside of the classroom. “Research is why I came to UW-Stevens Point. I was pleased with how easy it was to get involved.”
Doing undergraduate research with Caporale helped Fernholz, of West Salem, realize she wants to pursue a career in research. “It allowed me to get a sense of what a career in molecular biology research would be like.” A biochemistry and Spanish major, she graduated in May.
Helping students learn research techniques and be inspired to pursue research careers is a proud legacy for Caporale, who will retire in August.
Public health reports contain limited information regarding the psychological and neurological symptoms of tick-borne diseases (TBDs). Employing a mixed-method approach, this analysis triangulates three sources of symptomology and provides a comparison of official public health information, case reports, medical literature, and the self-reported symptoms of patients with Lyme disease and other TBDs.
Out of the fifteen neuropsychiatric symptoms reported in the medical literature for common TBDs, headaches and fatigue and/or malaise are the only two symptoms fully recognized by public health officials.
Lyme disease is the least recognized by public health officials for presenting with neuropsychiatric symptoms
Only headaches and fatigue are recognized as overlapping symptoms of Lyme disease
Comparisons from a patient symptoms survey indicate that self-reports of TBDs and the associated symptoms align with medical and case reports.
anxiety
depression
panic attacks
hallucinations
delusions
pain—ranging from headaches to neck stiffness and arthritis—are common among patients who report a TBD diagnosis.
Given the multitude of non-specific patient symptoms, and the number and range of neuropsychiatric presentations that do not align with public health guidance, this study indicates the need for a revised approach to TBD diagnosis and for improved communication from official public health sources regarding the wide range of associated symptoms.View Full-Text
He is asking China for full information, which is akin to asking the moon for cheese, according to a law professor, expert in public health law, and director of a WHO Collaborating Center on Public Health Law and Human Rights.
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According to a “senior European politician,” World Health Organization Director-General Tedros Adhanom Ghebreyesus confided to him in private that he believes COVID-19 was the result of a catastrophic accident at the Wuhan Institute of Virology in Wuhan, China.
But that’s not what the highly compromised WHO scientific advisory group concluded in 2020. After sharp criticism, the WHO set up another advisory group called SAGO, which released its preliminary report June 9, 2022 – which also found the lab leak theory to be unlikely despite the fact none of the three pieces of data that would support zoonotic origin have been identified.
SARS-CoV-2 has several mechanisms for targeting HERV-K102, a human replication-competent endogenous retrovirus that protects against viruses and is a crucial defense mechanism against severe COVID-19. This fact strongly supports a lab-leak hypothesis as the virus appears to have been designed to bypass this defense mechanism as selection of this trait could not have occurred in animals as only humans have HERV-K102 and the only way to give a bat-related coronavirus the ability to inhibit this mechanism is by passaging the virus through humanized mice, which has been done.Source
Since the identification of theSARS-CoV-2 in Wuhan, China, in January 2020 (1), the origin of the virus has been a topic of intense scientific debate and public speculation. The two main hypotheses are that the virus emerged from human exposure to an infected animal [“zoonosis” (2)] or that it emerged in a research-related incident (3). The investigation into the origin of the virus has been made difficult by the lack of key evidence from the earliest days of the outbreak—there’s no doubt that greater transparency on the part of Chinese authorities would be enormously helpful. Nevertheless, we argue here that there is much important information that can be gleaned from US-based research institutions, information not yet made available for independent, transparent, and scientific scrutiny.
When it comes to deciphering the origins of COVID-19, much important information can be gleaned from US-based research institutions—information that has yet to be made available for independent, transparent, and scientific scrutiny. Image credit: Dave Cutler (artist).
The data available within the United States would explicitly include, but are not limited to, viral sequences gathered and held as part of the PREDICT project and other funded programs, as well as sequencing data and laboratory notebooks from US laboratories. We call on US government scientific agencies, most notably the NIH, to support a full, independent, and transparent investigation of the origins of SARS-CoV-2. This should take place, for example, within a tightly focused science-based bipartisan Congressional inquiry with full investigative powers, which would be able to ask important questions—but avoid misguided witch-hunts governed more by politics than by science.
Essential US Investigations
The US intelligence community (IC) was tasked, in 2021 by President Joe Biden (4), with investigating the origin of the virus. In their summary public statement, the IC writes that “all agencies assess that two hypotheses are plausible: natural exposure to an infected animal and a laboratory-associated incident” (4). The IC further writes that “China’s cooperation most likely would be needed to reach a conclusive assessment of the origins of COVID-19 [coronavirus disease 2019].” Of course, such cooperation is highly warranted and should be pursued by the US Government and the US scientific community. Yet, as outlined below, much could be learned by investigating US-supported and US-based work that was underway in collaboration with Wuhan-based institutions, including the Wuhan Institute of Virology (WIV), China. It is still not clear whether the IC investigated these US-supported and US-based activities. If it did, it has yet to make any of its findings available to the US scientific community for independent and transparent analysis and assessment. If, on the other hand, the IC did not investigate these US-supported and US-based activities, then it has fallen far short of conducting a comprehensive investigation.
This lack of an independent and transparent US-based scientific investigation has had four highly adverse consequences. First, public trust in the ability of US scientific institutions to govern the activities of US science in a responsible manner has been shaken. Second, the investigation of the origin of SARS-CoV-2 has become politicized within the US Congress (5); as a result, the inception of an independent and transparent investigation has been obstructed and delayed. Third, US researchers with deep knowledge of the possibilities of a laboratory-associated incident have not been enabled to share their expertise effectively. Fourth, the failure of NIH, one of the main funders of the US–China collaborative work, to facilitate the investigation into the origins of SARS-CoV-2 (4) has fostered distrust regarding US biodefense research activities.
Much of the work on SARS-like CoVs performed in Wuhan was part of an active and highly collaborative US–China scientific research program funded by the US Government (NIH, Defense Threat Reduction Agency [DTRA], and US Agency for International Development [USAID]), coordinated by researchers at EcoHealth Alliance (EHA), but involving researchers at several other US institutions. For this reason, it is important that US institutions be transparent about any knowledge of the detailed activities that were underway in Wuhan and in the United States. The evidence may also suggest that research institutions in other countries were involved, and those too should be asked to submit relevant information (e.g., with respect to unpublished sequences).
Participating US institutions include the EHA, the University of North Carolina (UNC), the University of California at Davis (UCD), the NIH, and the USAID. Under a series of NIH grants and USAID contracts, EHA coordinated the collection of SARS-like bat CoVs from the field in southwest China and southeast Asia, the sequencing of these viruses, the archiving of these sequences (involving UCD), and the analysis and manipulation of these viruses (notably at UNC). A broad spectrum of coronavirus research work was done not only in Wuhan (including groups at Wuhan University and the Wuhan CDC, as well as WIV) but also in the United States. The exact details of the fieldwork and laboratory work of the EHA-WIV-UNC partnership, and the engagement of other institutions in the United States and China, has not been disclosed for independent analysis. The precise nature of the experiments that were conducted, including the full array of viruses collected from the field and the subsequent sequencing and manipulation of those viruses, remains unknown.
EHA, UNC, NIH, USAID, and other research partners have failed to disclose their activities to the US scientific community and the US public, instead declaring that they were not involved in any experiments that could have resulted in the emergence of SARS-CoV-2. The NIH has specifically stated (6) that there is a significant evolutionary distance between the published viral sequences and that of SARS-CoV-2 and that the pandemic virus could not have resulted from the work sponsored by NIH. Of course, this statement is only as good as the limited data on which it is based, and verification of this claim is dependent on gaining access to any other unpublished viral sequences that are deposited in relevant US and Chinese databases (7,8). On May 11, 2022, Acting NIH Director Lawrence Tabak testified before Congress that several such sequences in a US database were removed from public view, and that this was done at the request of both Chinese and US investigators.
Blanket denials from the NIH are no longer good enough. Although the NIH and USAID have strenuously resisted full disclosure of the details of the EHA-WIV-UNC work program, several documents leaked to the public or released through the Freedom of Information Act (FOIA) have raised concerns. These research proposals make clear that the EHA-WIV-UNC collaboration was involved in the collection of a large number of so-far undocumented SARS-like viruses and was engaged in their manipulation within biological safety level (BSL)-2 and BSL-3 laboratory facilities, raising concerns that an airborne virus might have infected a laboratory worker (9). A variety of scenarios have been discussed by others, including an infection that involved a natural virus collected from the field or perhaps an engineered virus manipulated in one of the laboratories (3).
Overlooked Details
Special concerns surround the presence of an unusual furin cleavage site (FCS) in SARS-CoV-2 (10) that augments the pathogenicity and transmissibility of the virus relative to related viruses like SARS-CoV-1 (11, 12). SARS-CoV-2 is, to date, the only identified member of the subgenus sarbecovirus that contains an FCS, although these are present in other coronaviruses (13, 14). A portion of the sequence of the spike protein of some of these viruses is illustrated in the alignment shown in Fig. 1, illustrating the unusual nature of the FCS and its apparent insertion in SARS-CoV-2 (15). From the first weeks after the genome sequence of SARS-CoV-2 became available, researchers have commented on the unexpected presence of the FCS within SARS-CoV-2—the implication being that SARS-CoV-2 might be a product of laboratory manipulation. In a review piece arguing against this possibility, it was asserted that the amino acid sequence of the FCS in SARS-CoV-2 is an unusual, nonstandard sequence for an FCS and that nobody in a laboratory would design such a novel FCS (13).
Fig. 1.
This alignment of the amino acid sequences of coronavirus spike proteins, in the region of the S1/S2 junction, illustrates the sequence of SARS-CoV-2 (Wuhan-Hu-1) and some of its closest relatives. The furin cleavage site (FCS) is indicated (PRRAR’SVAS), and furin cuts the spike protein between R and S, as indicated by the red arrowhead. Adapted from Chan & Zhan (15).
In fact, the assertion that the FCS in SARS-CoV-2 has an unusual, nonstandard amino acid sequence is false. The amino acid sequence of the FCS in SARS-CoV-2 also exists in the human ENaC α subunit (16), where it is known to be functional and has been extensively studied (17, 18). The FCS of human ENaC α has the amino acid sequence RRAR’SVAS (Fig. 2), an eight–amino-acid sequence that is perfectly identical with the FCS of SARS-CoV-2 (16). ENaC is an epithelial sodium channel, expressed on the apical surface of epithelial cells in the kidney, colon, and airways (19, 20), that plays a critical role in controlling fluid exchange. The ENaC α subunit has a functional FCS (17, 18) that is essential for ion channel function (19) and has been characterized in a variety of species. The FCS sequence of human ENaC α (20) is identical in chimpanzee, bonobo, orangutan, and gorilla (SI Appendix, Fig. 1), but diverges in all other species, even primates, except one. (The one non-human non-great ape species with the same sequence is Pipistrellus kuhlii, a bat species found in Europe and Western Asia; other bat species, including Rhinolophus ferrumequinem, have a different FCS sequence in ENaC α [RKAR‘SAAS]).
Fig. 2.
Amino acid alignment of the furin cleavage sites of SARS-CoV-2 spike protein with (Top) the spike proteins of other viruses that lack the furin cleavage site and (Bottom) the furin cleavage sites present in the α subunits of human and mouse ENaC. Adapted from Anand et al. (16).
One consequence of this “molecular mimicry” between the FCS of SARS CoV-2 spike and the FCS of human ENaC is competition for host furin in the lumen of the Golgi apparatus, where the SARS-CoV-2 spike is processed. This results in a decrease in human ENaC expression (21). A decrease in human ENaC expression compromises airway function and has been implicated as a contributing factor in the pathogenesis of COVID-19 (22). Another consequence of this astonishing molecular mimicry is evidenced by apparent cross-reactivity with human ENaC of antibodies from COVID-19 patients, with the highest levels of cross-reacting antibodies directed against this epitope being associated with most severe disease (23).
We do not know whether the insertion of the FCS was the result of natural evolution (2, 13)—perhaps via a recombination event in an intermediate mammal or a human (13, 24)—or was the result of a deliberate introduction of the FCS into a SARS-like virus as part of a laboratory experiment. We do know that the insertion of such FCS sequences into SARS-like viruses was a specific goal of work proposed by the EHA-WIV-UNC partnership within a 2018 grant proposal (“DEFUSE”) that was submitted to the US Defense Advanced Research Projects Agency (DARPA) (25). The 2018 proposal to DARPA was not funded, but we do not know whether some of the proposed work was subsequently carried out in 2018 or 2019, perhaps using another source of funding.
We also know that that this research team would be familiar with several previous experiments involving the successful insertion of an FCS sequence into SARS-CoV-1 (26) and other coronaviruses, and they had a lot of experience in construction of chimeric SARS-like viruses (27–29). In addition, the research team would also have some familiarity with the FCS sequence and the FCS-dependent activation mechanism of human ENaC α (19), which was extensively characterized at UNC (17, 18). For a research team assessing the pandemic potential of SARS-related coronaviruses, the FCS of human ENaC—an FCS known to be efficiently cleaved by host furin present in the target location (epithelial cells) of an important target organ (lung), of the target organism (human)—might be a rational, if not obvious, choice of FCS to introduce into a virus to alter its infectivity, in line with other work performed previously.
Of course, the molecular mimicry of ENaC within the SARS-CoV-2 spike protein might be a mere coincidence, although one with a very low probability. The exact FCS sequence present in SARS-CoV-2 has recently been introduced into the spike protein of SARS-CoV-1 in the laboratory, in an elegant series of experiments (12, 30), with predictable consequences in terms of enhanced viral transmissibility and pathogenicity. Obviously, the creation of such SARS-1/2 “chimeras” is an area of some concern for those responsible for present and future regulation of this area of biology. [Note that these experiments in ref. 30 were done in the context of a safe “pseudotyped” virus and thus posed no danger of producing or releasing a novel pathogen.] These simple experiments show that the introduction of the 12 nucleotides that constitute the FCS insertion in SARS-CoV-2 would not be difficult to achieve in a lab. It would therefore seem reasonable to ask that electronic communications and other relevant data from US groups should be made available for scrutiny.
Seeking Transparency
To date, the federal government, including the NIH, has not done enough to promote public trust and transparency in the science surrounding SARS-CoV-2. A steady trickle of disquieting information has cast a darkening cloud over the agency. The NIH could say more about the possible role of its grantees in the emergence of SARS-CoV-2, yet the agency has failed to reveal to the public the possibility that SARS-CoV-2 emerged from a research-associated event, even though several researchers raised that concern on February 1, 2020, in a phone conversation that was documented by email (5). Those emails were released to the public only through FOIA, and they suggest that the NIH leadership took an early and active role in promoting the “zoonotic hypothesis” and the rejection of the laboratory-associated hypothesis (5). The NIH has resisted the release of important evidence, such as the grant proposals and project reports of EHA, and has continued to redact materials released under FOIA, including a remarkable 290-page redaction in a recent FOIA release.
Information now held by the research team headed by EHA (7), as well as the communications of that research team with US research funding agencies, including NIH, USAID, DARPA, DTRA, and the Department of Homeland Security, could shed considerable light on the experiments undertaken by the US-funded research team and on the possible relationship, if any, between those experiments and the emergence of SARS-CoV-2. We do not assert that laboratory manipulation was involved in the emergence of SARS-CoV-2, although it is apparent that it could have been. However, we do assert that there has been no independent and transparent scientific scrutiny to date of the full scope of the US-based evidence.
The relevant US-based evidence would include the following information: laboratory notebooks, virus databases, electronic media (emails, other communications), biological samples, viral sequences gathered and held as part of the PREDICT project (7) and other funded programs, and interviews of the EHA-led research team by independent researchers, together with a full record of US agency involvement in funding the research on SARS-like viruses, especially with regard to projects in collaboration with Wuhan-based institutions. We suggest that a bipartisan inquiry should also follow up on the tentative conclusion of the IC (4) that the initial outbreak in Wuhan may have occurred no later than November 2019 and that therefore the virus was circulating before the cluster of known clinical cases in December. The IC did not reveal the evidence for this statement, nor when parts of the US Government or US-based researchers first became aware of a potential new outbreak. Any available information and knowledge of the earliest days of the outbreak, including viral sequences (8), could shed considerable light on the origins question.
We continue to recognize the tremendous value of US–China cooperation in ongoing efforts to uncover the proximal origins of the pandemic. Much vital information still resides in China, in the laboratories, hospital samples, and early epidemiological information not yet available to the scientific community. Yet a US-based investigation need not wait—there is much to learn from the US institutions that were extensively involved in research that may have contributed to, or documented the emergence of, the SARS-CoV-2 virus. Only an independent and transparent investigation, perhaps as a bipartisan Congressional inquiry, will reveal the information that is needed to enable a thorough scientific process of scrutiny and evaluation.
Odocoileus virginianus (white-tailed deer) is the primary host of adult Ixodes scapularis (deer tick). Most of the research into I. scapularis has been geographically restricted to the northeastern United States, with limited interest in Oklahoma until recently as the I. scapularis populations spread due to climate change. Ticks serve as a vector for pathogenic bacteria, protozoans, and viruses that pose a significant human health risk. To date, there has been limited research to determine what potential tick-borne pathogens are present in I. scapularis in central Oklahoma. Using a one-step multiplex real-time reverse transcription-PCR, I. scapularis collected from white-tailed deer was screened for Anaplasma phagocytophilum, Borrelia burgdorferi, Borrelia miyamotoi, Babesia microti, and deer tick virus (DTV). Ticks (n = 394) were pooled by gender and life stage into 117 samples. Three pooled samples were positive for B. miyamotoiand five pooled samples were positive for DTV. This represents a minimum infection rate of 0.8% and 1.2%, respectively. A. phagocytophilum, B. burgdorferi, and B. microti were not detected in any samples. This is the first report of B. miyamotoi and DTV detection in Oklahoma I. scapularis ticks. This demonstrates that I. scapularis pathogens are present in Oklahoma and that further surveillance of I. scapularis is warranted.
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**Comment**
A few points:
This article is based upon the faulty premise that somehow “climate change” is causing tick and disease proliferation. This has been proven to be false yet is continually regurgitated as truth. This; however, does not mean “the powers that be” are not committing heinous acts of “climate engineering” which IS causing very real destruction of life.
This recent article proves Spain has admitted recently spraying deadly chemtrails as part of a secret UN program to fight COVID.
Four state meteorological agency whistleblowers announced in 2015 that planes were regularly spraying lead dioxide, silver iodide, and diatomite throughout Spain to ward off rain and allow temperatures to riseto create a summery climate for tourism as well as the agricultural sector – producing cold drops of great intensity.
We’ve also been told ad nauseum that Lyme doesn’t exist in Oklahoma and while this research also didn’t find it, it did discover B miyamotoi which symptoms are similar to Lyme. But again, just because they didn’t find it, doesn’t mean it isn’t there. The black legged tick is abundant in Oklahoma.
Yuanjie Sun
Yoshihisa Koyama
Shoichi Shimada
Madison Area Lyme Support Group 